To investigate the mood response of schizophrenic subjects to psychostimulant challenge, 29 neuroleptic-treated subjects (22 with schizophrenia and 7 with schizoaffective disorder) in clinical remission received two infusions, one with methylphenidate 0.5 mg/kg and the other with normal saline, under double-blind conditions. Twenty-five of these subjects were withdrawn from neuroleptics and given a second set of double-blind infusions. Infusion mood responses were classified as euphoric, neutral, mixed or dysphoric. Subjects were also rated as either psychotic symptom activators to the infusion or no change in psychotic symptoms. Overall response by mood category was as follows: 35.2% euphoric, 50% neutral, 5.6% mixed and 9.3% dysphoric. Mood responses were not correlated with sex, methylphenidate plasma levels or diagnostic distinctions between schizophrenia and schizoaffective disorder. Although they occurred infrequently, dysphoric and mixed mood responses were associated with high rates of psychotic activation. Comparing subjects on and off neuroleptics, subjects on neuroleptics had more euphoric responses than the same subjects off neuroleptics. This increased number of euphoric responses in subjects taking neuroleptics compared to off neuroleptics suggests that neuroleptic treatment status may be an important factor in assessing psychostimulant use in schizophrenia patients.