Obesity is correlated with increased colorectal cancer (CRC) risk, but few studies have investigated lifetime body mass index (BMI) metrics and CRC risk. In a cohort of 139 229 subjects in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, we analysed the effects of life-course BMI trajectories on CRC risk. At 13 years of follow-up, 2031 subjects developed CRC. Compared with subjects who were never overweight/obese, subjects who first exceeded the threshold of 25 kg m-2 at age 20 had a higher CRC risk (HR = 1.28, 95% confidence interval (CI) = 1.11-1.48). A body weight gain of ≥15 kg between 20 and 50 years of age (HR = 1.34, 95% CI = 1.18-1.52) and baseline (HR = 1.24, 95% CI = 1.08-1.43) was significantly associated with increased CRC risk. BMI trajectory analyses revealed that the CRC risk increased gradually over the three BMI trajectories (HR = 1.11-1.27, Ptrend = 0.005) compared with subjects who maintained a normal BMI. Being overweight/obese at the onset of adulthood and BMI trajectories over the lifespan that result in obesity lead to an increased CRC risk.