S treptococcus pyogenes (group A Streptococcus [GAS]) causes a range of pyogenic, toxigenic, and immunologic diseases with varying degrees of severity, from pharyngitis and impetigo to necrotizing fasciitis and streptococcal toxic shock syndrome (1). Improved sanitation and increased availability of antimicrobial drugs have led to a decline in GAS incidence and virulence (2), but concern about invasive GAS (iGAS) has increased in recent decades (3). Each year, ≈500,000 deaths occur worldwide from GAS; 160,000 of these are from invasive infections, of which 97% occur in resource-limited countries (4). Some of the highest rates of iGAS occur in Indigenous populations within industrialized countries (5), most likely as a consequence of health disparities between general populations and marginalized peoples, in addition to a poorly understood host-pathogen relationship. In the United States, American Indians and Alaska Natives (AI/AN) suffer from high rates of iGAS, but epidemiologic and clinical data on GAS among these Indigenous populations is more sparse than it is in other industrialized nations (6). We highlight discordance between the substantial effect of iGAS on AI/AN and understanding of factors that influence iGAS disease in these vulnerable US populations and in other Indigenous persons. iGAS in the United States During the 1980s, the first reports of streptococcal toxic shock-like syndrome resulted in a resurgence in concern about GAS disease. A population-based study of iGAS in the United States found a stable annual incidence rate of 4.3 cases/100,000 population during 1985-1990 (7). Despite this stable rate, GAS disease increased, and multiorgan dysfunction and hypotension signaled an increase in GAS severity. This study prompted the Centers for Disease Control and Prevention (CDC) to add iGAS to the Active Bacterial Core surveillance (ABCs) program. The first survey, which assessed iGAS in the United States during 1995-1999, found an annual incidence of 2.2-4.8 iGAS cases/100,000 population (3). Rates were stable in 2 follow-up epidemiologic studies that showed iGAS incidence of 3.5 cases/100,000 population for 2000-2004 and 3.8 cases/100,000 population for 2005-2012 (1,8). The CDC reports suggested stability with unchanging rates and disease distribution. Each report concluded that iGAS incidence had been stable not only intrastudy but also across decades, starting with the work of Hoge et al. (7). The researchers referenced higher rates of iGAS among Indigenous populations of other countries, and ABCs data indicated that AI/AN make up <2% of the country but contributed 4% of iGAS cases during 2000-2012 (1,8). This finding provides at least inferential evidence of higher rates of iGAS among AI/ AN that warrants further investigation.