OBJECTIVES: The objective of this study was to characterize U.S. national trends of the incidence and cost of skin and soft tissue infections (SSTIs) in 2000 and 2012.   METHODS: We performed an analysis of nationally representative data from the Medical Expenditure Panel Surveys (MEPS) from 2000 and 2012. SSTIs were defined by Clinical Classification Software code 197. Expenditures in MEPS were defined as payments from all sources for hospital inpatient care, ambulatory care provided in offices and hospital outpatient facilities, care provided in emergency departments, and the retail purchase of prescribed medications. Expenditure data for 2000 were adjusted to 2012 dollars using the Consumer Price Index. RESULTS: The overall incidence of SSTIs increased 40% from 2.4 million in 2000 to 3.3 million in 2012. From 2000 to 2012, the incidence of patients with at least one hospital visit for SSTI increased 38%, ambulatory visits increased 46%, and emergency department visits increased 56%. The total spent on the treatment of SSTIs tripled, from $4.4 billion in 2000 to $13.8 billion in 2012. This was largely attributed to an 8-fold increase in ambulatory expenditures for SSTIs, from $975 million in 2000 to $7.9 billion in 2012. From 2000 to 2012, emergency department care expenditures increased 130%, inpatient hospitalization expenditures increased 56%, and retail prescription purchases increased 18%. The average expenditures for ambulatory visits increased 5-fold from $253 [standard error (SE) + $33] to $1,336 (SE + $240) per person, and average hospital expenditures increased 10% from $20,135 (SE + $3,997) to $22,706 (SE + $5,234) per person, between 2000 and 2012. CONCLUSIONS: The clinical and economic burden of SSTIs has significantly increased in the U.S., largely driven by a dramatic increase in the number and costs of SSTIs managed in the ambulatory setting.