Abstract Background: Obesity increases the risk of 13 cancer types. Given the long process of carcinogenesis, it is important to determine the impact of patterns of body mass over time. Methods: Using data from 30,377 participants in the Melbourne Collaborative Cohort Study, we identified body mass index (BMI) trajectories across adulthood and examined their association with the risk of obesity-related cancer. Participants completed interviews and questionnaires at baseline (1990–1994, age 40–69 years), follow-up 1 (1995–1998), and follow-up 2 (2003–2005). Body mass was recalled for age 18 to 21 years, measured at baseline, self-reported at follow-up 1, and measured at follow-up 2. Height was measured at baseline. Cancer diagnoses were ascertained from the Victorian Cancer Registry and the Australian Cancer Database. A latent class trajectory model was used to identify BMI trajectories that were not defined a priori. Cox regression was used to estimate HRs and 95% confidence intervals (CI) of obesity-related cancer risks by BMI trajectory. Results: Six distinct BMI trajectories were identified. Compared with people who maintained lower normal BMI, higher risks of developing obesity-related cancer were observed for participants who transitioned from normal to overweight (HR, 1.29; 95% CI, 1.13–1.47), normal to class I obesity (HR, 1.50; 95% CI, 1.28–1.75), or from overweight to class II obesity (HR, 1.66; 95% CI, 1.32–2.08). Conclusions: Our findings suggest that maintaining a healthy BMI across the adult lifespan is important for cancer prevention. Impact: Categorization of BMI by trajectory allowed us to identify specific risk groups to target with public health interventions.