© 2017, The Authors. Arthritis Care & Research published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology. Objective: This retrospective analysis examined how sustained remission impacted risk of serious infections in patients with rheumatoid arthritis (RA) enrolled in a clinical registry. Methods: Inclusion criteria included RA diagnosis, age ≥18 years, and ≥2 Clinical Disease Activity Index (CDAI) scores followed by a followup visit. Index date was the second of 2 visits in which a patient had sustained remission (CDAI ≤2.8), low disease activity (LDA; 2.8 < CDAI ≤10), or moderate-to-high disease activity (MHDA; CDAI >10). Followup extended from the index date until first serious infection (requiring intravenous antibiotics or hospitalization) or last followup visit. The crude incidence rate (IR) per 100 patient-years for serious infections was calculated for the sustained remission, LDA, and MHDA groups. The multivariable-adjusted incidence rate ratio (IRR) (adjusted for age, sex, and prednisone dose) compared serious infection rates across disease activity groups. Results: Most patients were female (>70%); mean age was approximately 60 years. The crude IR (95% confidence interval [95% CI]) per 100 patient-years for serious infections was 1.03 (0.85–1.26) in the sustained remission group (n = 3,355), 1.92 (1.68–2.19) in the sustained LDA group (n = 3,912), and 2.51 (2.23–2.82) in the sustained MHDA group (n = 5,062). Compared to sustained remission, the serious infection rate was higher in sustained LDA (adjusted IRR 1.69 [95% CI 1.32–2.15]). Compared to sustained LDA, the serious infection rate was higher in sustained MHDA (adjusted IRR 1.30 [95% CI 1.09–1.56]). Conclusion: In this study, lower RA disease activity was associated with lower serious infection rates. This finding may motivate patients and health care providers to strive for remission rather than only LDA.