Background. The objective was to evaluate the safety, reactogenicity and immunogenicity of the AMA-1-based blood-stage malaria vaccine FMP2.1/ AS02A in adults exposed to seasonal malaria. Methodology/Principal Findings. A phase 1 double Wind randomized controlled dose escalation trial was conductected in Bandiagara, Mall, West Africa, a rural town with intense seasonal transmission of Plasmodium falciparum malaria. The malaria vaccine FMP2.1/AS02A is a recombinant protein (FMP2.1) based on apical membrane antigen-1 (AMA-1) from the 3D7 clone of P. falciparum, adjuvanted with AS02A. The comparator vaccine was a cell-culture rabies virus vaccine (RabAvert). Sixty healthy, malaria-experienced adults aged 18-55 y were recruited into 2 cohorts and randomized to receive either a half dose or full dose of the malaria vaccine (FMP2.1 25 μg/A502A 0.25 ml. or FMP2.1 50 μg/AS02a 0.5 ml) or rabies vaccine given in 3 doses at 0, 1 and 2 mo, and were followed for 1 y. Solicited symptoms were assessed for 7 d and unsolicited symptoms for 30 d after each vaccination. Sewious adverse events were assessed throughout the study. Titers of anti-AMA-1 antibodies were measured by ELISA and p. falciparum growth inhibition assays were performed on sera collected at pre- and post-vaccination time points. Transient local pain and swelling were common and more frequent in both malaria vaccine dosage groups than in the comparator group. Anti-AMA-1 antibodies increased significantly in both malaria vaccine groups, peaking at nearly 5-fold and more than 6-foid higher than baseline in the half-dose and full-dose groups, respectively. Conclusion/Significance. The FMP2.1/AS02A vaccine had a good safety profile, was well-talerated, and was highly immunogenic in malaria-exposed adults, This malaria vaccine is being evaluated in Phase 1 and 2 trials in children at this site.