Left ventricular (LV) thrombi can arise in patients with ischemic and nonischemic cardiomyopathies. Anticoagulation is thought to reduce the risk of stroke or systemic embolism (SSE), but there are no high-quality data on the effectiveness of direct oral anticoagulants (DOACs) for this indication. To compare the outcomes associated with DOAC use and warfarin use for the treatment of LV thrombi. A cohort study was performed at 3 tertiary care academic medical centers among 514 eligible patients with echocardiographically diagnosed LV thrombi between October 1, 2013, and March 31, 2019. Follow-up was performed through the end of the study period. Type and duration of anticoagulant use. Clinically apparent SSE. A total of 514 patients (379 men; mean [SD] age, 58.4 [14.8] years) with LV thrombi were identified, including 300 who received warfarin and 185 who received a DOAC (64 patients switched treatment between these groups). The median follow-up across the patient cohort was 351 days (interquartile range, 51-866 days). On unadjusted analysis, DOAC treatment vs warfarin use (hazard ratio [HR], 2.71; 95% CI, 1.31-5.57; P = .01) and prior SSE (HR, 2.13; 95% CI, 1.22-3.72; P = .01) were associated with SSE. On multivariable analysis, anticoagulation with DOAC vs warfarin (HR, 2.64; 95% CI, 1.28-5.43; P = .01) and prior SSE (HR, 2.07; 95% CI, 1.17-3.66; P = .01) remained significantly associated with SSE. In this multicenter cohort study of anticoagulation strategies for LV thrombi, DOAC treatment was associated with a higher risk of SSE compared with warfarin use, even after adjustment for other factors. These results challenge the assumption of DOAC equivalence with warfarin for LV thrombi and highlight the need for prospective randomized clinical trials to determine the most effective treatment strategies for LV thrombi.