Background The emergence of community-associated methicillin-resistant Staphylococcus aureus (SA) and its role in skin and soft tissue infections (SSTIs) accentuated the role of SA-SSTIs in hospitalizations. Methods We used the Nationwide Inpatient Sample and Census Bureau data to quantify population-based incidence and associated cost for SA-SSTI hospitalizations. Results SA-SSTI associated hospitalizations increased 123% from 160,811 to 358,212 between 2001 and 2009, and they represented an increasing share of SA-hospitalizations (39% to 51%). SA-SSTI incidence (per 100,000 people) doubled from 57 in 2001 to 117 in 2009 (p< 0.01). A significant increase was observed in all age groups. Adults aged 75+ years and children 0–17 years experienced the lowest (27%) and highest (305%) incidence increase, respectively. However, the oldest age group still had the highest SA-SSTI hospitalization incidence across all study years. Total annual cost of SA-SSTI hospitalizations also increased and peaked in 2008 at 4.84billion,a44%increasefrom2001.In2009,theaverageassociatedcostofaSA-SSTIhospitalizationwas 11,622 (SE= 200).ConclusionTherehasbeenanincreaseintheincidenceandassociatedcostofSA-SSTIhospitalizationsinUSAbetween2001and2009,withthehighestincidenceincreaseseeninchildren0–17years.However,thegreatestburdenwasstillseeninthepopulationover75years.By2009,SSTIdiagnoseswerepresentinabouthalfofallSA-hospitalizations.