It has been proposed that antidepressants have neuroprotective effects on hippocampal neurons. To further test this hypothesis, brain-derived neurotrophic factor (BDNF), B cell lymphoma protein-2 (Bcl-2), and copper-zinc superoxide dismutase (Cu/Zn-SOD) were examined immunohistochemically in hippocampal neurons of Sprague-Dawley rats following daily treatment with 5 or 10 mg/kg of amitriptyline or venlafaxine for 21 days. At 5 mg/kg, both amitriptyline and venlafaxine increased the intensity of BDNF immunostaining in hippocampal pyramidal neurons, and the intensity of Bcl-2 immunostaining in hippocampal mossy fibers, but did not alter the Cu/Zn-SOD immunoreactivity. The high dose of venlafaxine, however, decreased the intensity of BDNF immunostaining in all subareas of the hippocampus and increased the intensity of Cu/Zn-SOD immunostaining in the dentate granular cell layer. The high dose of amitriptyline increased the intensity of Cu/Zn-SOD immunostaining, but did not affect the immunoreactivity of Bcl-2 or BDNF. These findings suggest that the chronic administration of amitriptyline or venlafaxine at 5 mg/kg, but not 10 mg/kg, may be neuroprotective to hippocampal neurons. These dose-related effects of antidepressant drugs on hippocampal neurons may have relevance to disparate findings in the field.