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Data guiding the duration and route of streptococcal bloodstream infection (BSI) treatment are lacking. We conducted a retrospective cohort study of adults hospitalized with uncomplicated streptococcal BSI in a large integrated healthcare system from 2013 to 2020. The exposures of interest were antibiotic duration (5-10 days vs. 11-15 days) and antibiotic route (oral switch vs. entirely intravenous). The primary outcome was a composite 90-day outcome comprised of all-cause mortality, recurrent streptococcal BSI, or readmission. We performed non-inferiority analyses for each exposure. Separate multivariable Cox proportional hazards regression models were constructed for each exposure. The antibiotic duration analysis included 1,407 patients (5-10 days, n = 246; 11-15 days, n = 1,161). We found that 5-10-day courses were non-inferior to 11-15-day courses ( P = 0.047). The antibiotic route analysis included 1,461 patients (oral switch, n = 1,112; entirely intravenous, n = 349). Oral step-down therapy did not meet the criteria for non-inferiority ( P = 0.06). In the adjusted models, no significant difference was found in the primary outcome rate by antibiotic duration or antibiotic route at discharge. We found that 5-10-day courses were non-inferior to longer courses, and thus may be a safe and effective treatment option in the treatment of uncomplicated streptococcal bacteremia. Randomized controlled trials are needed to confirm the equivalent outcomes with shorter regimens and to definitively determine the optimal antibiotic route on discharge., Competing Interests: D.S.C. was a principal investigator for a project supported by Janssen Pharmaceuticals, Inc. The other authors declare no competing interests.