Tricyclic antidepressant-morphine interactions have been extensively studied on pain tests but less often on tests predictive of antidepressant activity. The effects of clomipramine (CMI) and morphine were tested on the forced swimming test in mice after pretreatment with CMI, morphine or saline. Like CMI, though less so, morphine was significantly active. Morphine pretreatment partially inhibited the effect of CMI irrespective of the morphine pretreatment dose, but reduction of morphine activity by CMI was non-significant. Acquired tolerance to morphine occurred, but not to CMI. The mechanisms at work were discussed. CMI and desmethylclomipramine (DCMI) plasma levels remained the same after morphine pretreatment, ruling out a pharmacokinetic mechanism. The interaction implied involvement of opiate systems. CMI might have been acting on two different opiate receptor populations, one sensitive to morphine pretreatment, the other not. The mechanism of this action seems to be different from that of morphine.