There are eight phenylpropanolamine optical isomers related in structure to the central stimulants methamphetamine and amphetamine. Some of these are quite well known, such as (-)ephedrine, whereas others are relatively obscure, such as (-)cathine. Although certain of these phenylpropanolamines, such as (-)ephedrine and (+)cathine, retain central stimulant activity and are about 10- to 25-fold less potent than (+)amphetamine, the eight phenylpropanolamines have been compared only once before in drug discrimination studies. This latter study employed (-)ephedrine as the training drug. Because there are striking similarities between (-)ephedrine and (+)amphetamine as training drugs, it was of interest to determine and compare the effect of all eight phenylpropanolamines in (+)amphetamine trained animals. Using rats trained to discriminate 1 mg/kg of (+)amphetamine from saline vehicle under a variable interval 15-s (VI 15-s) schedule of reinforcement, the (+)amphetamine stimulus generalized only to (-)ephedrine (ED(50) = 4. 5 mg/kg) and (+)cathine (ED(50) = 8.0 mg/kg), and both agents were at least 10 times less potent that (+)amphetamine (ED(50) = 0.37 mg/kg). These results stand in contrast to those obtained with the (-)ephedrine-trained animals where the ephedrine stimulus generalized to all of the phenylpropanolamines except for (-)pseudoephedrine and (-)cathine. It is concluded that although there might be some similarity between the (-)ephedrine and (+)amphetamine stimuli, there are clear differences between them as determined in tests of stimulus generalization under the conditions employed.