Abstract Background Injection drug use has been associated with infection with invasive methicillin-resistant Staphylococcus aureus (iMRSA) and invasive group A Streptococcus (iGAS). In light of the ongoing opioid epidemic, we sought to describe the epidemiologic features of iGAS and iMRSA infections among persons who inject drugs (PWID) in the San Francisco Bay Area. Methods Active, population-based surveillance for iMRSA and iGAS was conducted in three California counties during 2008–2017. We defined a case as recovery of MRSA or GAS from a normally sterile site in a surveillance area resident ≥18 years of age. We collected demographic and clinical information and history of injection drug use (IDU) in the past 12 months. Trends in the incidence of infection were assessed using the Cochran-Armitage test for trend. Odds ratios (OR) and 95% Confidence Intervals (CI) were calculated comparing PWID and non-PWID. Results Of the 6,705 iMRSA and 1,691 iGAS cases identified during 2008–2017, 764 (11%) and 241 (14%), respectively, were among PWID. The proportion of iMRSA cases reporting IDU increased from 9.6% in 2008 to 12.9% (P = 0.017) in 2017 (Figure 1); no significant trend was observed for iGAS cases (Figure 2). Among iMRSA and iGAS cases, PWID cases were younger than non-PWID cases (iMRSA median 46 vs. 63 years, P < 0.0001; iGAS 41 vs. 57 years, P < 0.0001) and were more likely to be homeless (iMRSA OR 8.3, CI 6.7–10.2; iGAS OR 5.4, CI 4.0–7.2), and diagnosed with endocarditis (iMRSA OR 5.9, CI 4.8–7.3; iGAS OR 2.8, CI 1.3–6.4) and internal abscesses (iMRSA OR 4.3, CI 3.5–5.3; iGAS OR 3.4, CI 2.1–5.5) (Table 1). For iMRSA, PWID cases were more likely than non-PWID cases to be community-associated, (OR 2.5, CI 2.1–2.9) and diagnosed with septic arthritis (OR 2.4, CI 1.9–3.0). Conclusion The proportion of iMRSA cases reporting IDU significantly increased between 2008 and 2017, in the San Francisco Bay Area. iMRSA and iGAS cases among PWID are younger, more likely to be homeless, and diagnosed with endocarditis and internal abscesses. Prevention measures targeting this younger population who are experiencing homelessness and/or are injecting drugs, may limit severe manifestations of iMRSA and iGAS. These prevention measures should include support of safe injection practices. Disclosures All authors: No reported disclosures.