Urokinase-type plasminogen activator (u-PA) is a serine protease that has been implicated in cancer invasion and metastasis. We quantitated u-PA levels in normal colorectal mucosa, adenomatous polyps, and colorectal cancers and correlated these levels with clinicopathological features and patient survival. Detergent extracts were prepared from 133 colorectal cancers, 133 corresponding colorectal mucosal samples, and 15 synchronous adenomatous polyps. u-PA levels were determined using an ELISA, and a cancer:normal u-PA ratio was calculated for each case. u-PA levels were higher in cancers than in normal tissues, whereas adenomas had intermediate levels (P < 0.0001). u-PA levels were unrelated to clinical or pathological features. Survival was decreased in patients with a high cancer:normal u-PA ratio (P = 0.007). Multivariate survival analysis of patients undergoing curative surgery confirmed that the u-PA cancer:normal ratio was related to outcome (relative risk, 2.67; P = 0.02) and was independent of tumor stage (relative risk, 2.26; P = 0.03). Our study suggests that a high ratio of cancer to normal mucosal u-PA indicates an increased risk of colorectal cancer progression. Measurement of u-PA may provide useful prognostic information in patients undergoing curative surgery for colorectal cancer. The aggressive behavior of colorectal cancers with a high u-PA ratio suggests that the protease might be a suitable target for the development of therapeutic agents to prevent invasion and metastasis.