Serious infections due to group G streptococci have been infrequently reported. Fifteen such cases are described. Endovascular infection, particularly endocarditis, and septic arthritis were the most common clinical syndromes observed. Despite exquisite in vitro sensitivity of group G streptococci to penicillin G, the in vivo clinical response was disappointing in six of nine patients with either endocarditis or septic arthritis. The group G streptococcal isolates from the patients in this study were uniformly sensitive to the inhibitory and killing action of penicillin G, ampicillin, cefotaxime, cephalothin, cefoxitin, and vancomycin. In contrast, clindamycin, erythromycin, and chloramphenicol had relatively poor bactericidal activity against these strains, including several “tolerant” strains. Timed-kill studies with penicillin G revealed impaired killing of group G streptococci at in vitro conditions of high inocula and stationary growth phases. This may partially explain the poor clinical responses in cases of group G streptococcal endocarditis.