IMPORTANCE: Herpes zoster reactivation disproportionately affects patients with rheumatoid arthritis (RA). It is unclear whether anti-tumor necrosis factor (anti-TNF) therapy elevates herpes zoster risk. OBJECTIVES: To ascertain whether initiation of anti-TNF therapy compared with nonbiologic comparators is associated with increased herpes zoster risk. DESIGN, SETTING, AND PATIENTS: We identified new users of anti-TNF therapy among cohorts of patients with RA, inflammatory bowel disease, and psoriasis, psoriatic arthritis, or ankylosing spondylitis from 1998 through 2007 within a large US multi-institutional collaboration combining data from Kaiser Permanente Northern California, Pharmaceutical Assistance Contract for the Elderly, Tennessee Medicaid, and national Medicaid/Medicare programs. We compared herpes zoster incidence between new anti-TNF users (n=33,324) and patients initiating nonbiologic disease-modifying antirheumatic drugs (DMARDs) (n=25,742) within each inflammatory disease cohort (last participant follow-up December 31, 2007). Within these cohorts, we used Cox regression models to compare propensity score-adjusted herpes zoster incidence between new anti-TNF and nonbiologic DMARD users while controlling for baseline corticosteroid use. MAIN OUTCOME MEASURES: Incidence of herpes zoster cases occurring after initiation of new anti-TNF or nonbiologic DMARD therapy. RESULTS: Among 33,324 new users of anti-TNF therapy, we identified 310 herpes zoster cases. Crude incidence rates among anti-TNF users were 12.1 per 1000 patient-years (95% CI, 10.7-13.6) for RA, 11.3 per 1000 patient-years (95% CI, 7.7-16.7) for inflammatory bowel disease, and 4.4 per 1000 patient-years (95% CI, 2.8-7.0) for psoriasis, psoriatic arthritis, or ankylosing spondylitis. Baseline use of corticosteroids of 10 mg/d or greater among all disease indications was associated with elevated risk (adjusted hazard ratio [HR], 2.13 [95% CI, 1.64-2.75]) compared with no baseline use. For patients with RA, adjusted incidence rates were similar between anti-TNF and nonbiologic DMARD initiators (adjusted HR, 1.00 [95% CI, 0.77-1.29]) and comparable between all 3 anti-TNF therapies studied. Across all disease indications, the adjusted HR was 1.09 (95% CI, 0.88-1.36). CONCLUSION AND RELEVANCE: Among patients with RA and other inflammatory diseases, those who initiated anti-TNF therapies were not at higher risk of herpes zoster compared with patients who initiated nonbiologic treatment regimens.