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Injection drug use (IDU) is a risk factor for septic arthritis (SA) of native joints. Amid the opioid crisis, IDU rates have increased. This study assessed differences in pre-operative characteristics, microbial characteristics, and postoperative outcomes of 177 cases of SA treated operatively from 2015 to 2019 at 3 US hospitals, by self-reported IDU status. Forty cases (23%) involved patients who reported IDU. Patient characteristics, comorbidities, microbial characteristics, duration of hospital stay, discharge destination, follow-up rates, and rates of persistent/secondary infection were compared by self-reported IDU status. Compared with non–IDU-associated SA (non–IDU-SA), IDU-associated SA (IDU-SA) was associated with female sex ( P =.001), younger age ( P P P P =.04) and was more likely to involve methicillin-resistant Staphylococcus aureus ( P P P =.01). The 2 groups did not differ in terms of American Society of Anesthesiologists classification, joint involved, Gram stain positivity, presence of bacteremia, peripherally inserted central catheter placement, return to hospital within 3 months, or persistent/secondary positive results on culture within 3 months. Patients with IDU-SA were younger, were more likely to be female, had lower body mass index, and had fewer medical comorbidities but were more likely to use tobacco and to have a psychiatric diagnosis compared with patients with non–IDU-SA. Methicillin-resistant S aureus was more common in the IDU-SA group, as was discharge to a skilled nursing facility or against medical advice. Patients with IDU-SA were less likely to return for follow-up than patients with non–IDU-SA. [ Orthopedics . 2021;44(6):e747–e752.]