BACKGROUND: The emergence of community-associated methicillin-resistant S. aureus was associated with dramatically increased skin and soft tissue infection (SSTI) incidence in the first few years of the 21(st) century in the U.S. However, subsequent trends are poorly understood. METHODS: We examined ambulatory and inpatient data of over 48 million persons years aged 0-64 years from the HealthCore Integrated Research Database (HIRD) between 2005 and 2010. Data were extracted from medical, pharmacy, and eligibility databases. We quantified SSTI incidence, type, and complications and comparative incidence trends for urinary tract infections (UTIs) and pneumonia. RESULTS: A total of 2,301,803 SSTIs were identified. Most SSTIs (95 %) were treated in the ambulatory setting and most (60 %) were categorized as abscesses or cellulitis. During the study period, SSTI incidence remained relatively stable from 47.9 (95 % CI: 47.8-48.1) cases/1,000 PY in 2005 to 48.5 cases/1,000 PY (95 % CI: 48.3-48.6) in 2010). Persons aged 45-64 years had the highest incidence of both ambulatory-treated and inpatient-treated SSTIs (51.2 (95 % CI: 51.1-51.3) and 3.87 (95 % CI: 3.84-3.90) cases/1,000 PY, respectively). SSTI complications such as myositis, gangrene, and sepsis occurred in 0.93 % (95 % CI: 0.92-0.94 %) and 16.92 % (95 % CI: 16.87-16.97 %) of ambulatory-treated and inpatient-treated patients, respectively. SSTI incidence was approximately twice that of UTIs and tenfold of that of pneumonia. CONCLUSIONS: Among our large, diverse population of persons less than 65 years, SSTI incidence 2005 through 2010 has remained relatively constant at approximately 4.8 SSTIs per 100 person years, suggesting that previously observed increases in SSTI incidence remain sustained.