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Introduction: A hypoxic tumor microenvironment inhibits the normal functioning of immune cells. Studies have hypothesized that anticoagulants that can penetrate and bind to factor Xa in the tumor microenvironment, can enhance T-cell function and augment immunotherapy activity. This study compared objective response rate and progression-free survival of lung cancer patients on concomitant immunotherapy treated with direct-acting oral anticoagulants versus enoxaparin., Methods: This single-center retrospective study included 73 adults with stage-IV lung cancer who received at least two cycles of immunotherapy and one month of anticoagulant therapy with direct-acting oral anticoagulants (Arm A) versus enoxaparin (Arm B) between June 1, 2016, to September 30, 2022. Primary endpoint was objective response rate, and secondary endpoints were rates of complete response, progression-free survival, incidence of thrombotic events, and major bleeding., Results: Objective response rate at 6 months was 24.5% versus 25% while progression-free survival at 6 months was 54.7% versus 45% in Arm A versus Arm B, respectively. Complete response rates at 6 months were 7.5% in Arm A versus 0% in Arm B. One patient in Arm A and two in Arm B had a recurrent deep vein thrombosis. Nine patients in Arm A and two in Arm B were diagnosed with new deep vein thrombosis. One patient in Arm B was diagnosed with new pulmonary embolism. Two major bleeding events occurred in Arm B., Conclusions: Our study suggests a trend toward improved progression-free survival at 6 months with no new safety concerns in lung cancer patients on concurrent immunotherapy and direct-acting oral anticoagulants., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.