Background: Emerging reports suggest high rates of venous thromboembolism (VTE) and arterial thromboembolism (ATE) with immune checkpoint inhibitors (ICI) in pts with melanoma, but it is unclear whether these are truly increased compared to older systemic therapy approaches. We assessed the incidence of TE in melanoma pts on ICI, cytokine therapy (CY), and chemotherapy (chemo), and evaluated its impact on survival. Methods: We conducted a cohort study using the SEER-Medicare database to evaluate rates of TE in pts with melanoma treated from 2008-2019 with ICI (ipilimumab, nivolumab, pembrolizumab), CY (IL2, IFN), and/or chemo (antineoplastic agents, BRAF/MEK inhibitors) within two years of treatment initiation. TE including VTE events of deep venous thrombosis, pulmonary embolism, and ATE of MI, ischemic stroke, and transient ischemic attack were identified by at least two outpatient claims or one inpatient claim. Overall survival (OS) from treatment start was analyzed by time-varying Cox analysis. Results: The cohort comprised 13,124 pts with median age 75 (24-101) years and 68% male. Of these, 14.8% received ICI, 48.9% chemo, 1.7% CY, 31.8% chemo+ICI, and 2.8% chemo+CY. At treatment start, comorbidities included 72% of pts with hypertension, 33% cerebrovascular disease, 17% atrial fibrillation, 7.3% history of VTE, and 13.0% history of ATE. Overall, 11.4% were on anticoagulation and 5.2% on antiplatelet agents. Incidence rates of ATE and VTE after treatment start are shown (Table). VTE was highest at 3 months after starting therapy with 19.6 events per 100 person-years in those receiving chemo+ICI, 17.1 events with chemo, 15.4 events with ICI, 10.1 events with chemo+CY, and 7.7 events with CY. In multivariable analysis, VTE and ATE were associated with worse OS compared to patients without (HR 2.77 [95%CI, 2.50-3.08], and HR 2.53 [95%CI, 2.23-2.86], respectively). Conclusions: Systemic therapy with ICI and chemo, especially when exposed to both sequentially or concurrently, demonstrates a high incidence of TE in pts with melanoma. TE is associated with substantial worsening of survival. TE rates are not substantially increased with ICI in comparison to chemo. Further studies are needed to identify benefit of thromboprophylaxis.