Env-specific IgG and IgM were detected in 25 and 60%, respectively, of volunteers immunized with NYVAC expressing clade C gp120. The serum sample with the highest IgM titre but undetectable IgG neutralized the homologous isolate with a reciprocal IC90 titre of 7.8 in the absence of complement, and 24.4 in the presence of complement (P = 0.0003). These results suggest that vaccine-induced, Env-specific IgM may have antiviral activity and should be subjected to further investigation.