Using rats trained to discriminate 1 mg/kg of (+)amphetamine (ED 50 = 0.4 mg/kg) from saline vehicle in a two-lever drug discrimination procedure, it was shown that (−)ephedrine (ED 50 = 4.5 mg/kg), but not (+)ephedrine, substitutes for the (+)AMPH stimulus. It was also shown that caffeine (ED 50 = 12.9 mg/kg) can substitute for (+)amphetamine in a dose-related fashion. Doses of (−)ephedrine and caffeine, which produced ⩽1% drug-appropriate responding when administered alone, were able to enhance each other’s stimulus effects when administered in combination such that there was a twofold leftward shift in their respective dose–response curves. Furthermore, stimulus generalization occurred when a dose of caffeine that produced saline-appropriate responding when administered alone was administered in combination with (+)ephedrine. It would appear that low doses of (−)ephedrine and caffeine may mutually potentiate one another’s stimulus effects in (+)AMPH-trained rats, and that a combination of caffeine and (+)ephedrine result in altered stimulus character when compared to comparable doses of either agent administered alone.