Several clinical reports have suggested a beneficial effect of the addition of a low dose of an atypical antipsychotic drug, e.g., olanzapine (OLA), risperidone (RIS) to the ongoing treatment with antidepressant drugs, particularly of the selective serotonin reuptake inhibitors (e.g., fluoxetine, fluvoxamine and paroxetine) in the treatment of drug-resistant depression. In anxiety disorders, like post-traumatic stress disorder, some studies found that atypical antipsychotics improved certain symptoms, while others failed to reach the same conclusion. Preclinical evidence on the intrinsic anxiolytic-like property of atypical antipsychotics is also inconclusive. In the present study we examined the effect of treatment with OLA or RIS, given separately or jointly with fluoxetine (FLU) in the forced swimming test (FST, an animal model of depression) and in the elevated plus-maze test (an animal model of anxiety) in male Wistar rats. The obtained results showed that treatment with OLA or RIS (0.05 and 0.1 mg/kg) and FLU (10 mg/kg) did not change the immobility time of rats in the FST. Moreover, co-treatment with OLA or RIS and FLU produced antidepressant-like activity in the FST, and that serotonin 5-HT1A receptors might play some role in these effects. RIS (0.1 and 0.3 mg/kg), OLA (1 mg/kg) and FLU (5 and 10 mg/kg) induced anxiolytic-like effect in the elevated plus-maze test. In contrast, co-administration with OLA or RIS and FLU was ineffective in that test. This finding indicates that low doses of OLA or RIS enhances the action of FLU in an animal model of depression, and they may be of particular importance to the pharmacotherapy of drug-resistant depression. In contrast, OLA or RIS and FLU may each be clinically effective in treating anxiety disorders, but their effects may be attenuated in the combination treatment with both medications. This study was supported by grant POIG 01.01.02-12-004/09-00 from European Regional Development Fund.