12127 Background: The two most common therapies for the treatment of cancer-associated venous thromboembolism (VTE) are low molecular weight heparin (LMWHs) and direct oral anticoagulants (DOACs). However, there is a paucity of data on the optimal anticoagulation strategy specifically among patients receiving immune checkpoint inhibitors (ICIs). Therefore, we aimed to evaluate the comparable safety and efficacy of DOACs versus LMWHs in the treatment of VTE among patients receiving ICIs. Methods: We conducted a retrospective, propensity score-matched cohort study using the TriNetX Analytics Network, which contains de-identified data from over 120 healthcare institutions and 250 million patients. We included adult cancer patients who have received ICI therapy including nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, cemiplimab, ipilimumab, dostarlimab and who also received a diagnosis of VTE. Patients treated with DOACs were matched in a 1:1 ratio to patients treated with LMWHs based on the variables: age, sex, metastatic disease, cancer therapy, underlying comorbidities, Khorana score, and history of intracranial and gastrointestinal bleeding. The primary outcome was the occurrence of a new VTE, a composite of pulmonary embolism (PE) and deep venous thrombosis (DVT). The safety outcomes included all-cause mortality, intracranial hemorrhage, and gastrointestinal bleeding within 2 years following the start of anticoagulation therapy. Results: We matched 4608 ICI-treated patients on a DOAC to 4608 ICI-treated patients on a LMWH. In a Cox proportional hazard analysis, patients receiving DOACs or LMWH had a similar risk of a subsequent VTE event (Hazard ratio (HR), 1.13 [95% CI: 0.84-1.50]). When comparing different types of VTEs, the DOAC group was associated with a lower risk of PE (HR, 0.72 [95% CI: 0.54-0.96]) and a similar risk of DVT (HR, 0.87 [95% CI: 0.70-1.09]) compared to LMWHs. Furthermore, DOACs were associated with a lower risk of intracranial hemorrhage and all-cause mortality. There were no detectable differences in the risk of gastrointestinal bleeding between the two groups. Conclusions: DOACs were associated with a similar risk for subsequent VTE events but a lower risk of intracranial bleeding as well as an improvement in mortality compared to LMWHs among ICI-treated patients with a diagnosis of VTE. Prospective trials are needed to validate these findings. [Table: see text]