The authors examined whether smoking while wearing a transdermal nicotine patch over 32 h was well-tolerated and led to smoking suppression in heavy smokers with schizophrenia. In a crossover design, 10 male veteran smokers with schizophrenia were admitted for two brief inpatient stays to smoke while wearing a transdermal nicotine or placebo patch. Carbon monoxide in expired air, self-reported cigarettes per day, nicotine plasma levels, and psychiatric ratings were measured. Nicotine levels increased during active patch treatment, without evidence of nicotine toxicity. Psychiatric symptoms, carbon monoxide and cigarettes per day did not change, although eight subjects had a decrease in expired carbon monoxide on the active patch. Dyskinesias showed a small, but significant, increase during smoking plus active patch. The heaviest smokers (identified by placebo phase nicotine plasma level or CO level above group median; n = 5) had a statistically significant decrease in expired carbon monoxide of at least 20%. Smoking while wearing the nicotine patch over 32 h was well tolerated. Significant decreases in carbon monoxide smoking indices were seen for the heaviest smokers. These findings suggest further investigation of a smoking reduction intervention in this population.