AbstractIntroductionExcept for their role in bacterial endocarditis, non-pneumococcal Streptococcus mitis group (SMG) bacteria have traditionally been regarded as commensals of the oropharynx. Widespread adoption of matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry has increased identification of these organisms and has led to increased concern about their clinical significance. We evaluated SMG bacteremia in a large multicenter cohort to characterize associated clinical syndromes and better define their clinical relevance.MethodsWe performed a retrospective review of all adult patients from 2017 to 2025 who had SMG bacteremia at three hospitals within the Texas Medical Center. SMG bacteremia was defined as isolation of S. mitis, S. mitis/oralis, or S. mitis group as determined by MALDI-TOF. Clinical syndromes were identified through chart review and assigned using consistent classification approaches informed by physician documentation, imaging, and microbiologic data.ResultsAmong 253 patients, neutropenia-associated bacteremia was most common (29.6%) followed by pneumonia (9.5%), infective endocarditis (8.7%), skin, soft tissue, or bone infections (7.9%), and other identified sources (12%). No clear source was identified in 9.5% of cases. Only 22.9% were classified as contaminants. High-grade bacteremia was common, with 47% of cases having ≥ 3 positive blood culture bottles. In contrast, patients in whom SMG was regarded as contaminant nearly always had only a single bottle positive.ConclusionSMG bacteremia was associated with a broad spectrum of clinical syndromes, with most isolates being regarded as representing clinically significant infection.