Objective. To study the incidence, time trends, and outcomes of serious infections in people with osteoarthritis (OA). Methods. We used 1998.2016 US National Inpatient Sample (NIS) data. Using recommended weights, we examined the epidemiology of 5 types of serious infections requiring hospitalization in people with OA (opportunistic infections [OIs], skin and soft tissue infections [SSTIs], urinary tract infections [UTIs], pneumonia, and sepsis/bacteremia). We performed multivariable-adjusted logistic regression analyses to analyze factors associated with healthcare utilization (hospital charges, length of hospital stay, discharge to nonhome setting), and in-hospital mortality. Results. Of all serious infection hospitalizations, 46,708,154 were without OA and 3,258,416 had OA. People with OA were 16.4 years older, more likely to be female (52% vs 65%), White (59% vs 70%), have a Deyo-Charlson Comorbidity Index (DCCI) ≥ 2 (42% vs 51%), receive Medicare (54% vs 80%), and less likely to receive care at an urban teaching hospital (45% vs 39%). Serious infection rates per 100,000 NIS hospitalizations increased from the study period of 1998.2000 to 2015.2016: OI (from 4.5 to 7.2); SSTI (from 48.4 to 145.9); UTI (from 8.4 to 104.6); pneumonia (from 164.0 to 224.3); and sepsis (from 39.4 to 436.3). In multivariable-adjusted analyses, older age, higher DCCI, sepsis, northeast region, urban hospital, and medium or large hospital bed size were significantly associated with higher healthcare utilization outcomes and in-hospital mortality; Medicaid insurance, non-White race, and female sex were significantly associated with higher healthcare utilization. Conclusion. Serious infection rates have increased in people with OA. Association of demographic, clinic, and hospital variables with serious infection outcomes identifies potential targets for future interventions.