To examine a treatment for upper extremity impairment in stroke survivors that combines administration of cyproheptadine hydrochloride with repetitive practice focused on control of muscle activation patterns. Double-blind, randomized controlled trial. Laboratory within free-standing rehabilitation hospital. A total of 94 stroke survivors with severe, chronic hand impairment were randomly assigned to one of four treatment groups. Participants received either placebo or cyproheptadine hydrochloride in identical pill form. Daily dosage of cyproheptadine/placebo was gradually increased from 8 mg/day to 24 mg/day over three weeks and then maintained over the next 6 weeks while participant completed 18 therapy sessions. Therapy consisted of either: (1) active practice of muscle activation patterns to play "serious" computer games or control a custom hand exoskeleton or (2) passive, cyclical finger stretching imposed by the exoskeleton. Hand control was evaluated with the primary outcome measure of time to complete the Graded Wolf Motor Function Test (GWMFT) and secondary outcome measures including finger strength and spasticity. Across the 88 participants who completed the study, a repeated measures ANOVA revealed a significant effect of GroupxEvaluation interaction on GWMFT (F=1.996, p=0.026). The three groups receiving cyproheptadine and/or actively practicing muscle activation pattern control exhibited significant reduction in mean time to complete the GWMFT tasks; roughly one-third of these participants experienced at least 10% reduction in completion time. Gains were maintained at the one-month follow-up evaluation. The group receiving placebo and passive stretching did not show improvement. No significant differences among groups were observed in terms of changes in strength or spasticity. Despite chronic, severe impairment, stroke survivors were able to complete the therapy focused on muscle activations and achieved statistically significant improvement in hand motor control. Cyproheptadine hydrochloride affords a potential complementary treatment modality for stroke survivors with hand impairment.