Objective: The aim of our study was to determine the frequency of resistance to activated protein C (APC), factor V Leiden (FVL) and the prothrombin G20210A variant in patients with colorectal cancer. Methods: 74 patients with colorectal cancer and 192 colonoscopically selected controls were prospectively investigated for the presence of APC resistance, FVL and the prothrombin G20210A variant. APC resistance was measured as the ratio of activated partial thromboplastin times with and without APC (APC sensitivity ratio, APC-SR). The FVL and prothrombin G20210A variant were detected by a polymerase-chain-reaction-based technique. Results: FVL was detected in the heterozygous form in 4 of 74 cancer patients (5.4%) and in 7 of 192 controls (3.6%; p > 0.5, odds ratio: 1.51). After excluding patients and controls with FVL, APC-SR was below 2 in 6 of 70 cancer patients (8.5%) and in 1 of 185 controls (0.5%; p < 0.01, odds ratio: 17.25), and the mean value of APC-SR was significantly lower in cancer patients than the respective level of controls (2.8 vs. 3.7, p < 0.001). The G20210A mutation in the prothrombin gene was found in the heterozygous form in 2 of 74 patients with colorectal cancer (2.7%) and in 5 of 192 colonoscopically control subjects (2.6%; p > 0.5, odds ratio: 1.03). Conclusions: These findings suggest that patients with colorectal cancer have a high frequency of resistance to APC but no significant differences in the frequency of the FVL or G20210A mutation of the prothrombin gene compared to colonoscopically selected controls.