PD-1 pathway blockade has been shown to promote proatherogenic T-cell responses and destabilization of atherosclerotic plaques. Moreover, preclinical evidence suggests a potential synergy of antiplatelet drugs with immune checkpoint inhibitors (ICIs). We conducted an analysis within a prospective observational protocol (APOLLO study) to investigate the rates, predictors, and prognostic significance of thromboembolic events (TE) and thromboprophylaxis in patients with advanced NSCLC treated with ICIs. Among 217 patients treated between April 2014 and September 2018, 13.8% developed TE events. Current smoking status (HR 3.61 (95% CI 1.52-8.60), = 0.004) and high (>50%) PD-L1 (HR 2.55 (95% CI 1.05-6.19), = 0.038) resulted in being independent TE predictors. An increased risk of death following a diagnosis of TE (HR 2.93; 95% CI 1.59-5.42; = 0.0006) was observed. Patients receiving antiplatelet treatment experienced longer progression-free survival (PFS) (6.4 vs. 3.4 months, HR 0.67 (95% CI 0.48-0.92), = 0.015) and a trend toward better OS (11.2 vs. 9.6 months, HR 0.78 (95% CI 0.55-1.09), = 0.14), which were not confirmed in a multivariate model. No impact of anticoagulant treatment on patients' outcomes was observed. NSCLC patients treated with ICIs bear a consistent risk for thrombotic complications, with a detrimental effect on survival. The impact of antiplatelet drugs on ICIs efficacy deserves further investigation in prospective trials.