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Olanzapine/fluoxetine combination therapy is a widely prescribed antipsychotic-antidepressant regimen for treatment resistant depression and is reported to have a side effect of peripheral edema. The theoretical underpinnings of peripheral edema in association with olanzapine/fluoxetine combination therapy are still unclear. Although peripheral edema associated with olanzapine/fluoxetine combination is rarely reported, the mechanism of drug interaction and effect on cytochrome P450 enzymes may induce it. We review the case of a middle-aged patient, who presented with peripheral edema after the administration of olanzapine/fluoxetine combination therapy.