Background: Insulin sensitivity and cardiovascular risk profile were examined in 20 healthy, nonobese, middle-aged men who were long-term users of nicotine-containing chewing gum and in 20 matched control subjects who did not use nicotine. Methods and Results: Long-term use of nicotine-containing chewing gum was associated with insulin resistance and hyperinsulinemia. The degree of insulin sensitivity correlated negatively to the extent of nicotine use measured as plasma cotinine levels. Conclusions: These findings suggest that nicotine is the major constituent in cigarette smoke that leads to insulin resistance, metabolic abnormalities associated with the insulin resistance syndrome, and increased cardiovascular morbidity. Thus, the use of nicotine replacement therapy during smoking cessation should be transient and limited.