Antagonists of nicotine have been used in an attempt to resolve the continuing controversy about the role of nicotine as the primary reinforcer in cigarette smoking. Mecamylamine, an antagonist which readily penetrates to the central nervous system, increased the rate of cigarette smoking by about 30% in laboratory tests; this was accompanied by reduced blood pressure, impaired performance of a digit symbol substitution test, improved hand steadiness, and by dysphoria. The increased smoking may be regarded as self-titration with nicotine, an interpretation which receives some support from results obtained with pentolinium, an antagonist with predominantly peripheral actions. In the doses used, pentolinium did not affect smoking rate, blood pressure, or hand steadiness, but it impaired digit symbol performance and induced dysphoria. The different results with mecamylamine and pentolinium support previous evidence that the action of nicotine in the central nervous system has a small but clearly demonstrable role as a primary reinforcer of the smoking habit.