Debridement, antibiotics with implant retention (DAIR), and 2-stage revision are standard surgical interventions for treating knee periprosthetic joint infection (PJI). Patients with substance use disorder (SUD), especially addictive drug use disorder (DUD), have been shown to receive inferior medical care in many specialties compared with nonusers. The authors identified patients with a diagnosis of PJI after knee arthroplasty who received either DAIR or 2-stage revision with the Nationwide Inpatient Sample (NIS) database from 2010 to 2014. Patients were stratified into 2 groups, patients with DUD and nonusers, based on Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, criteria. Descriptive analysis was conducted to show the national trend for knee PJI treatment among the 2 patient groups. Multivariate logistic regression was used to compare the prevalence of DAIR and 2-stage revision between these 2 groups, adjusted for likely confounders, including age, sex, income, race, and comorbidities. Among the 11,331 patients with knee infection, 139 (1.23%) had DUD. Compared with nonusers, patients with DUD were significantly younger (P<.001), had more chronic conditions (P<.001), and were predominantly in lower income quartiles (P=.046). The 2 groups did not differ in sex and race (P=.072 and P=.091, respectively). The authors found that 30.22% of patients with DUD and 36.36% of nonusers received DAIR. The difference in these proportions was not statistically significant (P=.135). The results did not change after adjustment for confounding factors (P=.509). The findings suggested that bias does not exist among orthopedic surgeons who choose DAIR or 2-stage revision for knee PJI among patients with DUD. [Orthopedics. 2021;44(3):e385-e389.].