Resistance to fusidic acid among community methicillin susceptible Staphylococcus aureus (MSSA) isolates in the United Kingdom and prescriptions for fusidic acid have both doubled over the past 6 years. A retrospective case-control study was undertaken to test the hypothesis that the use of topical fusidic acid is associated with the isolation of resistant organisms. A statistically significant association was found between fusidic acid resistance in MSSA isolates and exposure to topical fusidic acid (odds ratio: 2.77, 95% CI 1.01-7.93, P = 0.027). This study demonstrates for the first time an association between the use of topical fusidic acid and resistance at the individual patient level and supports the hypothesis that the observed increase in resistance is causally associated with the increased use of topical fusidic acid.