Biological factors responsible for nicotine initiation and dependence are largely unknown. Men and women smoke differently, and may smoke for different reasons. Brain metabolic response to nicotine may explain gender differences in nicotine use. We used FDG-PET to measure brain metabolic response on placebo and following nicotine administered by patch in 42 females and 77 males (smokers and non-smokers) while performing a Continuous Performance Task (CPT) or the Bushman Competition and Retaliation Task (CRT). Nicotine administration affected brain metabolism much differently in males and females, and these differences were dependent on task and smoking history. In the placebo condition female smokers performing the CPT and female non-smokers performing the CRT consistently had higher brain metabolism than males, especially in the entire prefrontal system and the mid and anterior temporal lobe, language cortices, and related subcortical systems. The overall effect of nicotine was to decrease these gender differences in brain metabolism.