BACKGROUND: A variety of drugs impair motor recovery after sensorimotor cortex (SMCTX) injury in laboratory animals and may have similar effects in humans. METHODS: Rats (n = 142) underwent unilateral suction-ablation of the hindlimb SMCTX or sham lesion. After 24 hours, rats were given a single dose of placebo, haloperidol (0.1, 1.0, or 10.0 mg/kg, intraperitoneal), or clozapine (0.1, 0.5, 1.0, or 10.0 mg/kg, intraperitoneal), and motor recovery was measured. RESULTS: Neither haloperidol (analysis of variance [ANOVA] F[3, 12], P = 0.43) nor clozapine (ANOVA F[4, 19], P = 1.00) affected motor performance in controls. Haloperidol impaired motor recovery (ANOVA F[3, 42], P = 0.002) at each tested dose, with no differences between the doses. The effect persisted after 2 weeks. In contrast, although rats given a single dose of clozapine of 1.0 or 10.0 mg/kg had poorer recoveries (ANOVA F[4, 51], P = 0.014), only those given the highest dose differed from controls. The effect was no longer apparent after 2 weeks. CONCLUSION: Consistent with previous reports, haloperidol retards motor recovery after SMCTX injury in rats. In contrast, there was no detrimental effect of clozapine when given at low doses. The use of low doses of atypical antipsychotics such as clozapine may provide a safer alternative to haloperidol in the treatment of agitated stroke patients.