Background and Purpose: Lifarizine is a novel ion channel modulator which is neuroprotective in experimental global and focal ischemia, at doses that have minimal systemic vascular effects. This was a preliminary efficacy and safety study of lifarizine in human stroke. Methods: In a multicenter, randomized, double-blind, parallel-group study, subjects with symptoms and signs of first ischemic stroke were randomized to receive lifarizine (250 μg/kg, i.v. stat. plus 60 mg b.d. orally for 5 days) or matching placebo, after stratification for age (21–74 or ≥: 75 years) and for time since stroke onset (<6 or 6–12 h). Primary end points were safety of lifarizine and functional outcome at 13 weeks, using the modified Barthel Index and the Rankin Scale. Secondary measures included the National Institutes of Health and Canadian Neurological scales. Results: Of 147 patients recruited, 117 were evaluated for efficacy analysis. Lifarizine was well tolerated; a single seizure was attributed to active treatment. Biochemical and hematological indices were unchanged. Blood pressure fell over the study period, particularly in the lifarizine group. All-patient mortality during the 3-month study was 12/75 (16%) for lifarizine and 17/72 (24%) for placebo; amongst evaluable patients, mortality was 9/63 (14%) for lifarizine and 13/54 (24%) for placebo. At 13 weeks, the improvement in functional independence in the lifarizine group versus the placebo group was 16% greater by the Rankin Scale, p = 0.52, and 11% greater by the Barthel score, p = 0.55. Conclusions: Lifarizine was well tolerated. Mortality and functional assessment data showed favorable trends. Further studies are justified to examine the efficacy of lifarizine in acute stroke.