Background: Apixaban and rivaroxaban are two direct-acting oral anticoagulants (DOACs) recommended for thromboprophylaxis in cancer patients treated with chemotherapy. The objective was to assess the cost-utility of thromboprophylaxis with apixaban and rivaroxaban vs no thromboprophylaxis in ambulatory cancer patients starting chemotherapy with an intermediate-to-high risk of venous thromboembolism (VTE), Khorana score ≥ 2 points. Methods: A cost-utility analysis was performed from the perspective of Spain´s National Health System (NHS) using an analytical decision model in the short term (180 days) and a Markov model in the long term (5 years). Transition probabilities were obtained from randomized, double-blind, placebo-controlled clinical trials of apixaban and rivaroxaban in adult ambulatory patients with cancer at risk for VTE, treated with chemotherapy (AVERT and CASSINI trials). The costs (€ 2021) were taken from Spanish sources. The utilities of the model were obtained through the EQ-5D questionnaire. Deterministic (base case) and probabilistic (second-order Monte Carlo simulation) analyses were conducted. Results: In the base case, apixaban was dominant (with a gain of 0.005 QALY, quality-adjusted life years, and a saving of €59.49 per patient) compared to no prophylaxis. Rivaroxaban would be cost-effective (with a gain of 0.006 QALY and an additional expense of €116.23 per patient) with a cost per QALY gained of €18,747 compared to no prophylaxis. For an willingness to pay of €25,000 per QALY gained, the probability that apixaban or rivaroxaban will be cost-effective would be 62.6% and 51.9%, respectively. Conclusions: VTE thromboprophylaxis with apixaban generates savings and with rivaroxaban it generates an additional cost vs. no prophylaxis. With both DOACs, a modest QALY gain would be obtained. The probability that prophylaxis with apixaban would be cost-effective is 10.7% higher than with rivaroxaban.