Purpose: Cyclin D1and cyclin-dependent kinases (CDK) are commonly activated in colorectal cancer. The activity of cyclin D1can be blocked by CDK inhibitors, including p27 (CDKN1B) and p21 (CDKN1A, which is induced by p53). However, prognostic significance of tumoral cyclin D1 remains uncertain, and no previous study has considered potential confounding effect of p53, p21, p27, and related molecular events [microsatellite instability (MSI), CpG island methylator phenotype, and LINE-1hypomethylation]. Experimental Design:Among 602 colon cancer patients (stage I-IV) in two prospective cohort studies, cyclin D1overexpression was detected in 330 (55%) tumors by immunohistochemistry. Cox proportional hazard models computed hazard ratios (HR) of colon cancer - specific and overall mortalities, adjusted for patient characteristics and tumoral molecular features, including p53, p21, p27, cyclooxygenase-2, fatty acid synthase, LINE-1methylation, CpGislandmethylator phenotype, MSI, BMI, KRAS, and BRAF. Results: Cyclin D1 overexpression was associated with a low cancer-specific mortality in Kaplan-Meier analysis (P = 0.006), and in both univariate Cox regression [unadjusted HR, 0.64; 95% confidence interval (CI), 0.47-0.88; P = 0.0063] and multivariate analyses (adjusted HR, 0.57; 95% CI, 0.39-0.84; P = 0.0048). Similar findings were observed for an overall mortality (adjusted HR, 0.74; 95% CI, 0.57-0.98; P = 0.036). Notably, the effect of cyclin D1on survival might differ by MSI status (Pinteraction = 0.008). Compared with tumors that were both cyclin D1- negative and MSI-low/microsatellite stable, the presence of either cyclin D1or MSI-high or both seemed to confer better clinical outcome (adjusted HR point estimates, 0.10-0.65). Conclusions: Cyclin D1overexpression is associated with longer survival in colon cancer.