Continuous caffeine consumption with smoking cessation has been associated with more than doubled caffeine plasma levels. Such concentrations may be sufficient to produce caffeine toxicity symptoms in smoking abstinence conditions. To test whether caffeine abstinence influences smoking cessation, 162 caffeine-using smokers were enlisted from American Lung Association smoking cessation programs. Volunteers were randomly assigned by clinic to caffeine-use and caffeine-abstinence conditions and measured for 3 weeks post-smoking cessation, at 6 months and one year. Results showed a significant linear increase in caffeine sputum levels across 3 weeks post cessation for those who quit smoking and continued using caffeine. Three weeks after cessation, concentrations reached 203% of baseline for the caffeine user. Typical nicotine withdrawal symptoms occurred during the first 16 days of cessation. The caffeine abstainers, but not continued users of caffeine, reported increased fatigue during the first 3 days of cessation. Among complete caffeine abstainers, compared with caffeine users, there was a significant increase in fatigue, a decrease in stimulation, and a marginal increase in caffeine craving immediately following tobacco cessation. There were no differences between the groups on other withdrawal symptoms or in cessation success at 16 days, 6 months, or 12 months.