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Studies have evaluated various strategies to prevent venous thromboembolism (VTE) in neuro-oncology patients, without consensus.To perform a systematic review with cost-effectiveness analysis (CEA) of various prophylaxis strategies in tumor patients undergoing craniotomy to determine the safest and most cost-effective prophylaxis regimen.A literature search was conducted for VTE prophylaxis in brain tumor patients. Articles reporting the type of surgery, choice of VTE prophylaxis, and outcomes were included. Safety of prophylaxis strategies was determined by measuring rates of VTE and intracranial hemorrhage. Cost estimates were collected based on institutional data and existing literature. CEA was performed at 30 d after craniotomy, comparing the following strategies: mechanical prophylaxis (MP), low molecular weight heparin with MP (MP+LMWH), and unfractionated heparin with MP (MP+UFH) to prevent symptomatic VTE. All costs were reported in 2016 US dollars.A total of 34 studies were reviewed (8 studies evaluated LMWH, 12 for MP, and 7 for UFH individually or in combination; 4 studies used LMWH and UFH preoperatively). Overall probability of VTE was 1.49% (95% confidence interval (CI) 0.42-3.72) for MP+UFH, 2.72% [95% CI 1.23-5.15] for MP+LMWH, and 2.59% (95% CI 1.31-4.58) for MP, which were not statistically significant. Compared to a control of MP alone, the number needed to treat for MP+UFH is 91 and 769 for MP+LMWH. The risk of intracranial hemorrhage was 0.26% (95% CI 0.01-1.34) for MP, 0.74% (95% CI 0.09-2.61) for MP+UFH, and 2.72% (95% CI 1.23-5.15) for MP+LMWH, which were also not statistically significant. Compared to MP, the number needed to harm for MP+UFH was 208 and for MP+LMWH was 41. Fifteen studies were included in the final CEA. The estimated cost of treatment was $127.47 for MP, $142.20 for MP+UFH, and $169.40 for MP+LMWH. The average cost per quality-adjusted life-year for different strategies was $284.14 for MP+UFH, $338.39 for MP, and $722.87 for MP+LMWH.Although MP+LMWH is frequently considered the optimal prophylaxis for VTE risk reduction, our model suggests that MP+UFH is the safest and most cost-effective measure to balance VTE and hemorrhage risks in brain tumor patients at lower risk of hemorrhage. MP+LMWH may be more effective for patients at higher risk of VTE.