An 18-year-old man with attention-deficit-hyperactivity disorder (ADHD) was prescribed varenicline for smoking cessation. He quit smoking after 1 week of therapy and remained smoke free for the next 17 days. During that time, he had also been taking amphetamine-dextroamphetamine (Adderall) on work days for his ADHD. Because his supply of amphetamine-dextroamphetamine was diminishing, he took only half (30 mg every morning) of his prescribed dosage from days 4-12 of varenicline therapy. He further reduced his dosage to 15 mg every morning on days 13 and 14 of varenicline therapy, and his supply of amphetamine-dextroamphetamine was depleted on day 15. On day 23 of varenicline therapy, he received and filled a new prescription for amphetamine-dextroamphetamine and resumed his prescribed dosage (30 mg twice/day). He began smoking again within 48 hours. Rechallenge with varenicline while the patient continued to receive amphetamine-dextroamphetamine yielded similar results. Data suggest that addition of amphetamine to varenicline may negate the partial agonism of varenicline, resulting in elimination of the smoking-cessation aid's benefits. Other potential mechanisms for the drug interaction may also exist. Thus, varenicline may not aid smoking cessation in patients undergoing treatment with amphetamine and amphetamine-like drugs.