Objective To measure the incidence of treatment failure and associated costs in patients with methicillin-resistant Staphylococcus aureus (MRSA) skin and soft tissue infections (SSTIs). Methods This was a prospective, observational study in 13 primary care clinics. Primary care providers collected clinical data, wound swabs, and 90-day follow-up information. Patients were considered to have “moderate or complicated” SSTIs if they had a lesion ≥ 5 cm in diameter or diabetes mellitus. Treatment failure was evaluated within 90 days of the initial visit. Cost estimates were obtained from federal sources. Results Overall, treatment failure occurred in 21% of patients (n=21/98) at a mean additional cost of $1,933.71 per patient. Treatment failure occurred in 27% of patients in the moderate or complicated group and 11% of patients in the mild or uncomplicated group (p = 0.08). In a subgroup analysis of patients who received I&D, patients with moderate or complicated SSTIs had higher rates of treatment failure than patients with mild or uncomplicated SSTIs (36% vs. 10%; p = 0.04). Conclusions One in five patients presenting to a primary care clinic for a MRSA SSTI will likely require additional interventions as a result of treatment failure at an associated cost of almost $2,000 per patient. Baseline risk stratification and new treatment approaches are needed to reduce treatment failures and costs in the primary care setting.