Cannabis use has been found to stimulate appetite and potentially promote weight gain via activation of the endocannabinoid system. Despite the fact that the onset of cannabis use is typically during adolescence, the association between adolescence cannabis use and long-term change in body weight is generally unknown. This study aims to examine the association between adolescence cannabis use and weight change to midlife, while accounting for the use of other substances. The study applied 20 to 22 years of follow-up data on 712 Danish adolescents aged between 15 and 19 years at baseline. Self-reported height and weight, cannabis, cigarette and alcohol use, socioeconomic status (SES) and physical activity levels were assessed in baseline surveys conducted in 1983 and 1985. The follow-up survey was conducted in 2005. In total 19.1% (n = 136) of adolescents reported having used/using cannabis. Weight gain between adolescence and midlife was not related to cannabis exposure during adolescence in either crude or adjusted models, and associations were not modified by baseline alcohol intake or smoking. However, cannabis use was significantly associated with cigarette smoking (p<0.001) and alcohol intake (p<0.001) and inversely associated with physical activity levels (p = 0.04). In conclusion, this study does not provide evidence of an association between adolescence cannabis use and weight change from adolescence to midlife.