Smoking cessation is associated with increases in body weight, but little is known about the relationship between participation in a weight loss intervention and smoking. Objective: To determine whether (a) weight losses at 1 year differ as a function of baseline smoking status (never smoker, current smoker, ex-smoker) and (b) participation in a weight loss intervention affects smoking behavior. Method: This analysis addressed these questions using the publicly available database from Look AHEAD, a randomized trial comparing intensive lifestyle intervention (ILI) and diabetes support and education (DSE; control condition) among individuals with overweight/obesity and Type 2 diabetes, and included 4,387 participants who had self-reported smoking and objective weight measures available at baseline and at 1 year. Results: Although participants in ILI lost a significantly greater percentage of weight than those in DSE at 1 year (ILI, M = −8.8%, SD = 6.8; DSE, M = −0.7%, SD = 4.7), there were no differences in weight loss outcomes between never smokers (n = 2,297), ex-smokers (n = 2,115), and current smokers (n = 188) within either condition. Participation in ILI was not associated with compensatory smoking or likelihood of quitting smoking or relapsing. Conclusions: Smokers in a weight loss intervention had reductions in weight that were comparable to individuals who did not smoke without any evidence of compensatory smoking to manage eating and appetite. Smokers with obesity should be encouraged to pursue weight loss without concerns regarding the impact on smoking behavior.