Purpose <p>To evaluate the safety and efficacy of allogeneic fresh frozen plasma drops for the treatment of chronic ocular graft-versus-host disease (oGVHD).</p> Methods <p>In this prospective open-label institutional study, adult oGVHD patients were administered allogeneic fresh frozen 100% plasma (FFP) eye drops QID or more for 3 months, in addition to the patients’ usual treatment. The drops were prepared using a closed sterile tubing system (COL© System, Biomed Device Srl., Italy). The main outcome measures included the Ocular Surface Disease Index (OSDI), corneal fluorescein staining National Eye Institute (NEI) scale, basal tear secretion test, and functional assessment of cancer therapy–bone marrow transplant (FACT-BMT) questionnaire.</p> Results <p>This study included 25 patients (49 eyes). OSDI scores decreased from 53 ± 26 at baseline to 32 ± 22 after 1 month and 30 ± 23 after 3 months (<i>P</i> &lt; 0.0001), and fluorescein staining NEI grade decreased from 7.04 ± 3.51 at baseline to 5.5 ± 3.1 after 1 month (<i>P</i> &lt; 0.0001) and 5.3 + 3.1 after 3 months (baseline to 3 months, <i>P</i> &lt; 0.0001; one month to 3 months, <i>P</i> = 0.64). Mean basal tear secretion was 4.65 ± 3.4&#xa0;mm at baseline and 6.5 ± 4.7&#xa0;mm after 3 months (<i>P</i> = 0.002). The FACT-BMT scores did not change significantly from baseline to 3 months (106.3 ± 22 vs. 112 ± 20, <i>P</i> = 0.08). A subset of eight patients who were using scleral or bandage contact lenses concurrently showed significant improvement, and four of them were managed without lenses during the study period. No significant adverse events were noted.</p> Conclusion <p>Allogeneic FFP eye drops are safe and effective in the treatment of chronic oGVHD.</p> Trial registration <p>The trial is listed from 10/2020 in the Israeli Ministry of Health Clinical Trials Registry (MOH_2021-09-30_010276).</p>