p21 (Cyclin-dependent kinase inhibitor-1A, CDKN1A or CIP1) plays a role in regulating cell cycle, and its expression is lost in most colorectal cancers. p21 Is related with energy balance status, cellular senescence, and stem cell aging. Thus, the influence of p21 loss on tumor behavior and clinical outcome may be modified by patient age and body mass index (BMI). Using 647 colon cancers in two independent prospective cohorts, p21 loss was observed in 509 (79%) tumors by immunohistochemistry. Cox proportional hazard models computed hazard ratio (HR) for death, adjusted for potential confounders, including p53, cyclin D1, KRAS, BRAF, PIK3CA, LINE-1 hypomethylation, CpG island methylator phenotype (CIMP), and microsatellite instability (MSI). p21 Loss was independently associated with low colon cancer-specific mortality [HR, 0.58; 95% confidence interval (95% CI), 0.38-0.89; adjusted for the covariates including MSI, CIMP, and LINE-1 methylation]. The prognostic effect of p21 loss differed significantly by age at diagnosis (P(interaction) < 0.0001) and BMI (P(interaction) = 0.002). The adjusted HR for cancer-specific mortality (p21 loss versus p21 expression) was 4.09 (95% CI, 1.13-14.9) among patients <60 year old and 0.37 (95% CI, 0.24-0.59) among patients >or=60 year old. The adverse prognostic effect of obesity was limited to p21-expressing cases (adjusted HR, 5.85; 95% CI, 2.28-15.0; BMI, >or=30 versus <30 kg/m(2)), but no such effect was observed among p21-lost cases. In conclusion, p21 loss in colon cancer is associated with longer survival among patients >or=60 year old, whereas it is associated with shorter survival among patients <60 year old. Patient BMI also differentially influences prognosis according to p21 CDKN1A status. Our data suggest host-tumor interactions influencing tumor aggressiveness.