Objective: Pathological gambling is associated with elevated proportions of nicotine dependence, and tobacco smoking in pathological gamblers has been associated with increased problem-gambling severity. This study examined the addition of N-acetylcysteine to imaginal desensitization in adults with co-occurring nicotine dependence and pathological gambling. Method: Twenty-eight individuals with co-occurring DSM-IV nicotine dependence and pathological gambling who were receiving behavioral therapy were recruited from December 2009 to February 2012 and randomized to augmentation with N-acetylcysteine or placebo in an 12-week, double-blind trial. Subjects were assessed with measures of nicotine and gambling severity and followed for 3 months after treatment. The primary outcomes were the Fagerstrom Test for Nicotine Dependence and the pathological gambling adaptation of the Yale-Brown Obsessive-Compulsive Scale. Results: During the first 6 weeks, there was a significant benefit of N-acetylcysteine treatment versus placebo on Fagerstrom Test for Nicotine Dependence total scores (t = -2.224; P = .031). After the initial 6 weeks, all subjects significantly (P < .001) benefited from imaginal desensitization. During the 3-month follow-up, there was a significant additional benefit for N-acetylcysteine versus placebo on measures of problem-gambling severity (t = 2.069; P = .043). Conclusions: N-acetylcysteine treatment during therapy facilitates long-term application of behavioral therapy techniques once patients are in the community after therapy has been completed.