We describe the first reported case of bacterial pyomyositis of the right thigh caused by Streptococcus anginosus (S. milleri group) in an HIV-infected patient. The clinical presentation was complicated by multiple ring-enhancing lesions detected on magnetic resonance imaging of the brain. Evaluation for central nervous system toxoplasmosis,syphilis, and cryptococcal infection was negative. Aggressive antibiotic therapy directed against S. anginosus and surgical debridement were limb salvaging. Clinicians should considerS. anginosus as a causative pathogen in HIV-associated pyomyositis, particularly in complex presentations. Prompt surgical drainage may minimize complications due to S. anginosus, a pathogen associated with significant sequelae due to its invasive nature.