Study of the last period of Isidore's life is associated with a number of problems, the unambiguous resolution of which sometimes has seemed unattainable. First of all, they are: lack of published sources on the Roman Curia life in the 1440–60's, and in general insufficient historiography information concerning the convocation of the Council of Mantua and the Greeks in Italy after the fall of Constantinople. Having studied the available sources, the author concludes that the last period of Isidore's life was devoted to propaganda of the Union in the territory of Byzantine Empire; Isidore carried out a full-fledged activity as Cardinal of the Roman Church first in the rank of Cardinal-Presbyter, and from 1451 — Cardinal-Bishop. Roman popes sent various blessings to Isidore, giving him temples, monasteries and whole dioceses "in feeding". At the end of his life, in 1459, "the Ruthenian Cardinal" got a title of the Latin Patriarch (the titular Patriarch) of Constantinople, already conquered by the Turks, against which Isidore fought desperately in 1453, taking most active part in defending the city from the onslaught of Turkish troops. During the seizure of Constantinople, Cardinal Isidore nearly died, was sold into slavery, he stayed unrecognized because of the wound on his head which prevented him from being executed by Sultan, so Isidore happily escaped. When the capital of the Roma state fell, the question of Union lost its original relevance, but until the end of his days Cardinal Isidore did not give up hope for a revival of the Empire and was desperately doing his utmost. In the 1450–60's Isidore tried to organize, together with Bessarion of Nicaea, Pope Nicholas V, Callixtus III and Pius II a new Crusade against the Turks; he also took part in the Council of Mantua, though all these efforts never produced any significant result. The last days of his life Cardinal Isidore spent in Rome, and there he was buried: first in the Church of the Holy Apostles, and later — in the Cathedral Basilica of St. Peter.
Some attention of historiography has been given to the issue of the library and literary heritage of Isidore of Kiev, however the available studies are devoted either to his writings in general and become already outdated, or to his individual treatises, which makes it impossible to get a complete and distinct idea of Isidore as a prominent bibliophile and literary figure of the late Byzantine period. For his long life Isidore had managed to collect or work with an impressive number of books. Isidore made some notes in most of these manuscripts, part of the manuscripts was copied by his own hand, and some manuscripts were taken from the Papal library in the last decade of Isidore's life. At the moment, scientists have more than 160 codes that Cardinal was dealing with; the number of the books read by Isidore puts him on a par with such outstanding minds of the past as St. Photius of Constantinople and Michael Psellos.
Analysis of the Isidore's library allows to reveal the scope of his interests more or less clearly and to understand the features of a late-Byzantine intellectual in general. The range of his reading was extremely broad and included books of philosophical, historical, rhetorical, astrological and astronomical, natural-science and theological subjects. In fact there were only few manuscripts of theological content that passed through Isidore's hands or were kept in his personal library. This was probably due to the fact that basically Isidore collected books of the humanities and natural sciences, and he could refer to theological and patristic books any time in monastery or other institutional libraries. Anyway, a number of patristic books in Greek, taken by Isidore in the Papal library in 1455, can confirm his interest in the theological subject. Probably, there could have been much more books of that kind, but the Papal library was just started, so the number of books in Greek could be very limited.
Metropolitan Cardinal Isidore left behind a significant literary heritage, which, although inferior in terms of the amount of works to his younger contemporaries, such as St. Mark of Ephesus, Patriarch of Constantinople Gennadios II Scholarios or Bessarion of Nicaea, nevertheless, occupies a prominent place in the late Byzantine literature of the first half of the 15th century. The author has identified 52 works covering various literary genres: panegyrics in honor of Byzantine and German emperors; letters in Greek as well as letters translated into Latin, Italian and Slavic; theological, hymnographic and historical canonical works. All works are attributed to Isidore thanks to the surviving autographs, although no work has an inscription of his full name, with the exception of messages from Buda and to the Kholmsk elders.