We investigated the depression induced by human interferons using the forced swimming test in mice. Intravenous (i.v.) administration of interferon-alpha s (natural interferon-alpha, recombinant interferon-alpha-2a and recombinant interferon-alpha-2b, 600-60000 IU/kg) increased the immobility time in the forced swimming test in a dose-dependent manner, but natural interferon-beta and recombinant interferon-gamma-1a did not affect the immobility time. The increase in the immobility time induced by recombinant interferon-alpha-2b peaked at 15 min after dosing. Administration of recombinant interferon-alpha-2b (6000 IU/kg, i.v.) once daily for 7 consecutive days increased the immobility time, but natural interferon-beta and recombinant interferon-gamma-la did not. Recombinant interferon-alpha-2b in combination with the anti-depressants imipramine (10 mg/kg, i.p.) and mianserin (20 mg/kg, i.p.) did not increase the immobility time. These results suggest that interferon-alpha has a greater potential for inducing depression than interferon-beta and -gamma, and that anti-depressants are effective against interferon-alpha-induced depression.