Abstract Background: Medical patients may benefit from anticoagulant prophylaxis of venous thromboembolism (VTE), but assessment of thrombotic risk is complex. I describe a method for estimating the minimum thrombotic risk required to ensure that a reasonable benefit–hazard ratio is maintained. Methods: An equation was derived relating baseline VTE risk and a minimum acceptable benefit–hazard ratio (R), defined as ‘pulmonary embolus (PE) alone’, ‘PE or symptomatic proximal deep venous thrombosis (DVT)’, or ‘PE or any symptomatic DVT’ prevented per major bleeding. The equation was used to estimate the relative risk (RR) of thromboembolism required for net benefit (main outcome measure). The PREVENT study was the primary data source, backed by data from two meta-analyses. Results: For R ranging from 3 to 10, the RR required for net beneficial prophylaxis was 6.5–21.6 (PE alone); 3.0–9.9 (PE or symptomatic proximal DVT); and 2.3–7.6 (PE or any symptomatic DVT), respectively. These RR are possible only in the presence of risk factors of high weighting. Sensitivity analysis showed that the findings were robust to changes in baseline assumptions related to thrombosis and bleeding rates. Conclusion: A method for risk assessment for medical thromboprophylaxis has been developed. The results suggest that only a minority of medical patients with high RR should receive prophylaxis.