OBJECTIVE: To study the incidence, time-trends and outcomes of serious infections in people with osteoarthritis. METHODS: We used the 1998-2016 U.S. National Inpatient Sample data. We examined the epidemiology of five hospitalized, i.e., serious infections (opportunistic infections (OI), skin and soft tissue infections (SSTI), urinary tract infection (UTI), pneumonia, and sepsis/bacteremia) in people with osteoarthritis, using recommended weights. We performed multivariable-adjusted logistic regression analyses to analyze factors associated with healthcare utilization (hospital charges, length of hospital stay, discharge to non-home setting), and in-hospital mortality. RESULTS: Of all serious infection hospitalizations, 46,708,154 were without osteoarthritis, and 3,258,416 had osteoarthritis. Respectively, people with OA were 16 years older, more likely to be female (52% vs. 65%), White (59% vs. 70%), have Deyo-Charlson index score ≥2 (41% vs 51%), Medicare (54% vs. 80%), and less likely to receive care at an urban teaching hospital (45% vs. 39%). Serious infection rates /100,000 NIS hospitalizations increased from 1998-2000 to 2015-2016: OI from 4.5 to 7.2; SSTI, 48.3 to 145.8; UTI, 8.4 to 104.6; pneumonia, 164.0 to 224.3; sepsis, 39.4 to 436.3. In multivariable-adjusted analyses, older age, higher Deyo-Charlson score, sepsis, Northeast region, urban hospital and medium or large hospital bed size were significantly associated with higher healthcare utilization outcomes and inhospital mortality; and Medicaid insurance, non-White race, and female sex with higher healthcare utilization. CONCLUSION: Serious infection rates have increased in people with osteoarthritis. Association of demographic, clinic and hospital variables with serious infection outcomes identifies potential targets for future interventions.