The acquisition of morphine and nicotine conditioned place preference (CPP) and cross-tolerance between the response of two drugs was studied in mice. A biased CPP paradigm was used to study the effect of the agents. Morphine (5 mg/kg) and nicotine (1 mg/kg) induced CPP. Naloxone (0.5, 1 and 2 mg/kg), but not mecamylamine (0.025, 0.05 and 0.1 mg/kg), induced conditioned place aversion (CPA). Both antagonists reversed CPP induced by morphine and nicotine. Administration of one daily dose of morphine (12.5, 25 or 50 mg/kg) for 3 days or nicotine (0.5, 1 or 2 mg/kg) three times a day for 12 days, in order to develop tolerance to the drugs, reduced the conditioning induced by morphine (5 mg/kg) or nicotine (1 mg/kg). CPA-induced by naloxone was reduced in animals, which were rendered tolerant to morphine (50 mg/kg) or nicotine (2 mg/kg). Mecamylamine, however, which did not induce any response in the nontolerant mice, elicited CPP in the tolerant animals. It is concluded that there may be a cross-tolerance between morphine- and nicotine-induced CPP.