The decades before prostate cancer diagnosis represent an etiologically relevant time period for prostate cancer carcinogenesis. However, the association of weight gain in young adulthood with subsequent biochemical recurrence among men with prostate cancer is not well studied, particularly among smokers. We conducted a prospective cohort study of 1,082 men with prostate cancer and treated with either radical prostatectomy or radiation between 2003 and 2010. The association of weight at age 20, weight at age 50 and weight change from age 20 to age 50 with biochemical recurrence was assessed using Cox Proportional Hazards with adjustment for confounders. Stratum-specific hazard ratio (HR) estimates by smoking status were evaluated. In the overall cohort, weight at age 20 (HR per 30 kg: 1.56, 95% confidence interval (CI): 1.02, 2.38, p-trend: 0.039), weight at age 50 (HR per 30 kg: 1.80, 95% CI: 1.32, 2.47, p-trend: <0.001) and weight change from age 20 to age 50 (HR per 30 kg: 1.84, 95% CI: 1.24, 2.74, p-trend: 0.003) were associated with biochemical recurrence. In stratified analyses, weight change from age 20 to age 50 was significantly associated with biochemical recurrence only in former smokers (HR per 30 kg: 3.87, 95% CI: 1.88, 8.00, p-trend: <0.001) and ever smokers (HR per 30 kg: 2.38, 95% CI: 1.27, 4.45, p-trend: 0.007). No significant association was observed between weight gain in young adulthood and biochemical recurrence in never smokers. Our study adds further evidence that weight gain during early adult years conveys long-term risk for adverse cancer outcomes.