Enantiomers of tripmeperidine were prepared and the absolute configuration was determined by degradation of piperidinol [(+)-7] to (R)-3-dimethylamino-2-methylpropiophenone. The analgetic potency of the 2S,4S,5R isomer, (+)-13, is approximately equal to morphine and nine times that of its enantiomer. The absolute stereoselectivity of trimeperidine and that reported for α-prodine is qualitatively the same and the conformational features of the more potent enantiomers are also very similar. The results suggest that the antipodal stereoselectivity of trimeperidine is controlled primarily by the configuration and conformation of groups attached to the C-4 and C-5 chiral centers and that the 2-Me group plays a relatively minor role in the drug-receptor interaction. The present study lends further support to an earlier proposal that potency differences between enantiomeric 4-phenylpiperidines are due to the ability of the receptor to discriminate between the enantiotopic edges of the piperidine ring and to conformational factors.