The author tested the hypothesis that a history of drug-induced antagonism of alcohol impairment would enhance alcohol tolerance in humans. Groups of participants (N = 21) repeatedly performed a psychomotor task under different drug treatments: 0.65 g/kg alcohol, 4 mg/kg caffeine, or both drugs combined. Tolerance to a 0.65 g/kg alcohol dose challenge was then tested. Results showed that a history of combined alcohol and caffeine administrations increased alcohol tolerance compared with an exposure history to either drug alone. The findings contribute to the understanding of the complexities of polydrug use history and provide a useful model to examine how alcohol tolerance might be affected by a history of coadministration with other drugs (e.g., cocaine and nicotine).