Both, underuse and overuse of thromboprophylaxis in hospitalised medical patients is common. We aimed to explore clinical factors associated with the use of pharmacological or mechanical thromboprophylaxis in acutely ill medical patients at high (Geneva Risk Score ≥ 3 points) vs low (Geneva Risk Score < 3 points) risk of venous thromboembolism. Overall, 1,478 hospitalised medical patients from eight large Swiss hospitals were enrolled in the prospective Explicit ASsessment of Thromboembolic RIsk and Prophylaxis for Medical PATients in SwitzErland (ESTIMATE) cohort study. The study is registered on ClinicalTrials.gov, number NCT01277536. Thromboprophylaxis increased stepwise with increasing Geneva Risk Score (p< 0.001). Among the 962 high-risk patients, 366 (38 %) received no thromboprophylaxis; cancer-associated thrombocytopenia (OR 4.78, 95 % CI 2.75-8.31, p< 0.001), active bleeding on admission (OR 2.88, 95 % CI 1.69-4.92, p< 0.001), and thrombocytopenia without cancer (OR 2.54, 95 % CI 1.31-4.95, p=0.006) were independently associated with the absence of prophylaxis. The use of thromboprophylaxis declined with increasing severity of thrombocytopenia (p=0.001). Among the 516 low-risk patients, 245 (48 %) received thromboprophylaxis; none of the investigated clinical factors predicted its use. In conclusion, in acutely ill medical patients, bleeding and thrombocytopenia were the most important factors for the absence of thromboprophylaxis among high-risk patients. The use of thromboprophylaxis among low-risk patients was inconsistent, without clearly identifiable predictors, and should be addressed in further research.