AIM:Using nicotine gum can reduce the amount of weight gained when quitting. Here we examine the relationship between weight gain and use of adequate amounts of gum. To mitigate the confounders associated with correlational analyses, we contrast the effects of active gum and placebo, and analyze outcomes prospectively. DESIGN AND SETTING:Randomized double-blind placebo-controlled trial of nicotine gum. Participants were instructed to use nine to 15 pieces of gum/day for the first 2 months of treatment. PARTICIPANTS:Participants (n = 103) were randomized to either active (2 mg or 4 mg) or placebo gum. MEASUREMENTS:We examined the effect on weight gain of the interaction between treatment (active versus placebo) and daily gum use [≥9 pieces/day (compliant use) versus < 9 pieces/day]. FINDINGS:After 30 days of abstinence, smokers treated with active gum had not gained significantly less weight than those on placebo (1.1 kg versus 1.6 kg, P = 0.175). However, a significant compliance-treatment interaction was observed (P = 0.005): active gum users who used ≥9 pieces/day during the first 14 days of treatment had gained less weight at follow-up (0.6 kg versus 1.6 kg for those who used <9 pieces/day, P = 0.017), but participants randomized to the placebo group saw no such benefit from compliant use. A similar compliance-treatment interaction (P = 0.046) was also observed when the effect of compliance was examined within active treatment (2 mg versus 4 mg). CONCLUSIONS:When smokers are quitting, those who use more pieces of nicotine gum experience less weight gain in the first 30 days. This relationship is not seen for smokers on placebo gum.