C-reactive protein is a biomarker indicating inflammation in the body. We measured plasma C-reactive protein to assess whether this biomarker could predict subsequent colorectal cancer incidence. A nested case-control study was conducted within a Japan Public Health Center-based prospective study. During a 11.5-year follow-up, 375 newly diagnosed colorectal cancers were identified in a cohort of 38,373 adults who had returned the baseline questionnaire and provided blood samples. Two controls were selected from the cohort for each case matched by age, sex, study area, date of blood drawn, and fasting time at blood donation. The odds ratio of colorectal cancer for plasma C-reactive protein was estimated using a conditional logistic regression model adjusted for pack-years of smoking, body mass index, alcohol consumption, physical exercise, and family history of colorectal cancer. The highest quartile group of plasma C-reactive protein was significantly associated with colorectal cancer compared with the lowest group (odds ratio, 1.6; 95% confidence interval, 1.1-2.5; P(trend) = 0.053). The association became clearer after excluding cases of rectal cancer (P(trend) = 0.041) and limiting colorectal cancer to the intramucosal type (P(trend) = 0.017). This association was unchanged after deletion of the first 2-year cases. In conclusion, plasma levels of C-reactive protein were associated with a subsequent risk of colon cancer. Inflammation may be involved at the early stage of colon tumor growth.