The Infectious Disease Society of America (IDSA) publishes guidelines regularly for the management of skin and soft tissue infections; however, the extent to which practice patterns follow these guidelines and if this can affect treatment failure rates is unknown. We observed the treatment failure rates from a multicentre retrospective ambulatory cohort of adult emergency department patients treated for a non-purulent skin infection. We used multivariable logistic regression to examine the role of IDSA classification and whether adherence to IDSA guidelines reduced treatment failure. A total of 759 ambulatory patients were included in the cohort with 17.4% failing treatment. Among all patients, 56.0% had received treatments matched to the IDSA guidelines with 29.1% over-treated, and 14.9% under-treated based on the guidelines. After adjustment for age, gender, infection location and medical comorbidities, patients with a moderate infection type had three times increased risk of treatment failure (adjusted risk ratio (aRR) 2.98; 95% confidence interval (CI) 1.15-7.74) and two times increased risk with a severe infection type (aRR 2.27; 95% CI 1.25-4.13) compared with mild infection types. Patients who were under-treated based on IDSA guidelines were over two times more likely to fail treatment (aRR 2.65; 95% CI 1.16-6.05) while over-treatment was not associated with treatment failure. Patients 70 years of age had a 56% increased risk of treatment failure (aRR 1.56; 95% CI 1.04-2.33) compared with those < 70 years. Following the IDSA guidelines for non-purulent SSTIs may reduce the treatment failure rates; however, older adults still carry an increased risk of treatment failure.