A double-blind, randomized, placebo-controlled clinical trial, involving two Italian centers, was carried out to evaluate the efficacy and safety of the monosialoganglioside GM1 in acute ischemic stroke. A total of 112 consecutive patients were recruited. The treatment (GM1 or placebo) was intravenously administered for 3 weeks and the follow-up lasted for 6 months. Semiquantitative clinical evaluations were performed on admission at the end of treatment (day 21) and at the end of follow-up (day 180), by using the Frithz-Werner Scale for the neurological recovery and the Barthel Index for the activities of daily living. On day 21, the statistical analysis showed a significant neurological improvement (p < 0.01) in the Frithz-Werner Scale in favor of the GM1 group. On day 180, the difference between the two groups was not significant for the Frithz-Werner Scale, while it reached significance for the activities of daily living (Barthel Index) in favor of the GM1-treated group (p < 0.05).