A small subgroup of patients treated with lower-leg cast immobilization develops venous thromboembolism (VTE). (1) Identify risk factors for VTE in patients with cast immobilization, (2) assess the effectiveness of thromboprophylaxis in low- and high-risk groups, and (3) validate the performance of the L-TRiP(cast) score. Data from the POT-CAST trial were used. A total of 1,519 patients with lower-leg cast immobilization were randomized to a prophylactic dose of low-molecular-weight heparin or no treatment. symptomatic VTE within 3 months. Absolute risks (ARs) were determined for low- and high-risk subgroups. For several risk factors, relative risks (RRs) for VTE were estimated with corresponding 95% confidence intervals (CIs). For validating the L-TRiP(cast) score, a discrimination and calibration analysis were performed. Patients with a body mass index of > 30 kg/m2 and those with a VTE in their family history had an increased VTE risk, RR 3.8 (95% CI, 1.5-9.4) and RR 2.4 (95% CI, 1.0-5.6), respectively. Concerning injury-specific risk factors, patients with an Achilles tendon rupture or those who were surgically treated had the highest risk of VTE, AR at 8.5% (95% CI, 3.7-16.1) and AR 3.5% (95% CI, 1.3-7.5), respectively. There were no subgroups in which thromboprophylaxis was effective for prevention of symptomatic VTE. The area under the curve for the L-TRiP(cast) score was 0.69 (95% CI, 0.58-0.80). Thromboprophylaxis was not effective for VTE prevention following lower-leg cast immobilization in any risk category. Low- and high-risk individuals could be identified using the L-TRiP(cast) score. The best treatment strategy for these patients is yet to be determined. Georg Thieme Verlag KG Stuttgart · New York.