We investigated the effect of slow metabolism, predicted by CYP2A6 genotypes resulting in ≤50% activity, on smoking behaviour and treatment outcome with the nicotine patch and spray. CYP2A6 slow versus normal metabolizers had lower metabolic activity, indicated by the 3-hydroxycotinine/cotinine ratio, and smoked fewer cigarettes/day. With the nicotine patch, slow metabolizers maintained greater nicotine levels and percent nicotine replacement compared to normal metabolizers while using equal numbers of patches/week. With the nicotine spray slow metabolizers achieved similar nicotine levels and percent nicotine replacement to normal metabolizers by using fewer sprays/day. A low 3-hydroxycotinine/cotinine metabolite ratio (low CYP2A6 activity) predicted greater abstinence on the patch compared to high CYP2A6 activity but not on the spray. Thus, slow metabolism predicted greater nicotine levels, and cessation on the nicotine patch, while with the spray (dose titration) nicotine levels and cessation were similar between the groups. Thus, rates of nicotine metabolism influence, in part, smoking behaviour and cessation with nicotine replacement therapy.