Putative extracellular lipoproteins made by group A Streptococcus (GAS) are the focus of this study, which was designed to identify new candidate vaccine antigens. Bioinformatic analysis of a serotype M1 GAS strain identified 30 open-reading frames encoding putative lipoproteins. The genes encoding the mature form of 29 of these proteins were cloned, and 16 recombinant proteins were overexpressed in Escherichia coli and purified to apparent homogeneity. The genes encoding these 16 proteins were highly conserved in GAS strains for which genome sequence data are available (serotypes M1, M3, M5, M12, M18, and M28). Mice inoculated subcutaneously with GAS and humans with GAS pharyngitis and invasive infections seroconverted to most of the 16 recombinant proteins, which indicates that these lipoproteins were produced during infection. The blood of mice actively immunized with 5 of the 16 recombinant proteins had significantly (P<.05) increased growth-inhibitory activity, compared with the blood of unimmunized mice, which identified these proteins as potential new vaccine candidates