The phenomenon of unidirectional non-cross tolerance (UNCT) to etorphine was observed in adult male rats tolerant to morphine. Using a morphine pellet (four 75 mg morphine pellets) implantation protocol, a 10-fold increase in the analgesic ED50 value, obtained by tail-flick assay, was observed for morphine sulfate, with no alteration in analgesic ED50 value for etorphine. After etorphine pellet (two 60 micrograms pellets) implantation, no significant change in the ED50 value for etorphine was observed, but the ED50 value for morphine increased 15-fold. Both morphine and etorphine pellet-implanted animals, challenged with naloxone, showed similar qualitative signs of precipitated withdrawal. This seeming dissociation obtained by demonstration of physical dependence in the absence of tolerance to etorphine has its basis in the UNCT phenomenon. Thus, appropriate experimental paradigms must be included when evaluating tolerance to avoid specious conclusions.