Background: VTE in cancer significantly contributes to morbidity and a worse overall prognosis. Little is known about the incidence of VTE in melanoma pts receiving IO. This study aims to assess the incidence of VTE in melanoma pts on IO, interrogate potential association with specific therapies, and ascertain its prognostic utility. Methods: We conducted a retrospective cohort study of melanoma pts who received any IO including ipilimumab (ipi), nivolumab (nivo) or pembrolizumab (pembro) from July 2015 to December 2017 at the Cleveland Clinic. VTE including deep venous thrombosis and pulmonary embolism were identified by chart review. VTE-free survival and overall survival (OS) were estimated by Kaplan-Meier and Cox proportional hazard models; association between VTE and IO was examined using the Pearson’s chi-squared test. Results: This cohort comprised 219 pts with median age of 65 years (range 24-92) and 66.7% male. Pembro was most common (36.5%), followed by ipi/nivo (26.9%), ipi (21.9%), and nivo (14.6%). Most had distant metastatic disease (79.9%), and 16.4% had brain metastases. VTE occurred in 14.2% (n = 31) of pts on therapy. Of those with VTE, 12 (38.7%) were receiving ipi/nivo and 19 (61.3%) single agent IO. Median VTE-free time was 4.9 months on ipi/nivo compared to 9.2 months on single agent IO (p = 0.05). The 6-month VTE-free survival was 18.5% for ipi/nivo and 71.8% for single agent IO. Among pts with distant metastatic disease, ipi/nivo was significantly associated with earlier time to VTE when adjusted for age, gender, and presence of brain metastases, (median VTE-free time 4.9 months vs. 9.3; p = 0.024; HR 2.96 [95% CI, 1.15-7.59]). Among pts without brain metastases, VTE was associated with worse OS (median OS 1.3 years vs. NR; p<0.001; HR 3.47 [95% CI, 1.66-7.24]). Conclusions: VTE risk may be elevated for melanoma pts on IO, specifically those receiving ipi/nivo. Further studies are needed to identify pathophysiology, risk factors, and benefit of thromboprophylaxis in this setting.