We have previously observed that, while the impairing effects of amitriptyline on inhibitory avoidance in mice are consistently observed, those of acute fluoxetine are negligible. Two experiments were designed to investigate whether a regular dose of fluoxetine potentiates the effect of a low dose of amitriptyline that is ineffective when administered alone. Male and female CD1 mice were administered i.p. 30 min before training, as follows. In the first experiment, they were injected with saline, one of three doses of amitriptyline (2.5, 5, 10mg/kg), one dose of fluoxetine (15 mg/kg), or a combination of amitriptyline (2.5mg/kg) and fluoxetine (15 mg/kg). In the second experiment, the mice were injected with saline, amitriptyline (2.5mg/kg), one of three doses of fluoxetine (10, 15, 20mg/kg), or a combination of 2.5mg/kg of amitriptyline and one of the three mentioned doses of fluoxetine. Drug doses were selected based on previous experiments in our laboratory reported in other publications. The behavioural procedure used to test the effects of these treatments was step-through inhibitory avoidance. The joint administration of amitriptyline 2.5mg/kg and fluoxetine 15 mg/kg had a clear impairing effect on inhibitory avoidance as observed in the two experiments. The dose of 2.5mg/kg of amitriptyline, given alone, was ineffective. Doses of 5mg/kg, or higher, of amitriptyline impaired inhibitory avoidance. The only effect detected when fluoxetine was administered separately was in the males of the experiment 1, which exhibited less avoidance than controls. Our preclinical research throws light on the benefits of the combined administration of antidepressants.