Obesity is a risk factor for colorectal cancer. However, the effect of body weight change on colorectal cancer is uncertain. This study aimed to investigate the relationship between difference in body mass index and the risk of colorectal cancer. In this nationwide population-based cohort study, participants of the national cancer screening program in 2005 and 2009 were enrolled. Difference of body mass index was calculated from screening data from 2005 and 2009. Participants were divided into four groups according to direction of obesity status: non-obese/non-obese, non-obese/obese, obese/non-obese, and obese/obese. The effect of differences in body mass index on colorectal cancer was analyzed. Among 3,858,228 participants, 47,894 (1.24%) participants were newly diagnosed with colorectal cancer during the 9.2 years of follow-up. The incidence of colorectal cancer was higher in the obese/obese group than the non-obese/non-obese group (hazard ratio = 1.08 [1.06–1.11],Ptrend < 0.001). The men in the obese/obese group had a higher risk of colon cancer than women (hazard ratio = 1.13 [1.10–1.17] in men, and hazard ratio = 1.04 [1.01–1.18] in women,P= 0.001). Persistent obesity was associated with a higher risk of incidence of colorectal cancer.