Objective: Evidences from cultured cells and animal models of ischemia suggest that lithium has neuroprotective and neurotrophic effects and may play a desirable role in reducing infarct volume and even improving the brain insults from stroke. The aim of this study was to evaluate the efficacy of lithium in early motor recovery of patients after ischemic stroke.Methods: Eighty patients with first ever stroke, allocated randomly in lithium, 300 mg twice daily, or placebo. Treatment was initiated 48 hours after stroke and continued for 30 days. Modified National Institute of Health Stroke Scale (mNIHSS) and hand subsection of Fugl-Meyer Assessment (hFMA) were used to evaluate impairment on the fifth and 30th day of treatment.Results: Sixty-six subjects (32 subjects in the lithium group and 34 subjects in the placebo group) completed the study. There were no significant differences in the improvement in mNIHSS (P=0.40) and hFMA (P=0.07) after 30 days. However, a subgroup analysis showed that patients with cortical strokes in the lithium group had significantly better improvement in both mNIHSS and hFMA in comparison to the placebo group (P=0.003). Approximately 44% (n=14) of patients in the lithium group, mainly from the cortical stroke subgroup, regained more than 25% of full function based on hFMA, whereas this rate in the placebo group was 14.7% (n=5; P=0.009).Conclusion: The observed discrete difference between the lithium group and the placebo group in the cortical stroke subgroup may suggest an enhanced motor recovery after stroke by using an early treatment with a low dose of lithium carbonate. However, a larger trial with more patients with cortical stroke is needed to investigate this effect better.