Nicotine has reinforcing effects, but there are thousands of other compounds in tobacco, some of which might interact with nicotine reinforcement. This rat study was conducted to determine if nicotine self-administration is altered by co-administration of the complex mixture of compounds in tobacco smoke extract (TSE). Female Sprague-Dawley rats were tested for self-administration of low doses of nicotine (3 or 10 µg/kg/infusion) at three different rates of reinforcement (FR1, FR3 and FR5) over three weeks either alone or together with the complex mixture of tobacco smoke extract (TSE). Rats self-administering 3 µg/kg/infusion of nicotine alone showed a rapid initiation on an FR1 schedule, but declined with FR5. Rats self-administering nicotine in TSE acquired self-administration more slowly, but increased responding over the course of the study. With 10 µg/kg/infusion rats self-administered significantly more nicotine alone than rats self-administering the same nicotine dose in TSE. Rats self-administering nicotine alone took significantly more infusions with the 10 than the 3 µg/kg/infusion dose, whereas rats self-administering nicotine in TSE did not. Nicotine in TSE led to a significantly greater locomotor hyperactivity at a dose of 0.1 mg/kg compared to rats that received nicotine alone. Rats self-administering nicotine alone had significantly more responding on the active vs. inactive lever, but rats self-administering the same nicotine doses in TSE did not. Self-administration of nicotine in a purer form appears to be more clearly discriminated and dose-related than nicotine self-administered in the complex mixture of TSE.