Background: Using data from an observational study in which the effectiveness of a guideline for eradication of methicillin-resistant Staphylococcus aureus (MRSA) carriage was evaluated, we identified variables that were associated with treatment failure. Methods: A multivariate logistic regression model was performed with subgroup analyses for uncomplicated and complicated MRSA carriage (the latter including MRSA infection, skin lesions, foreign-body material, mupirocin resistance and/or exclusive extranasal carriage) and for those treated according to the guideline (i.e. mupirocin nasal ointment and chlorhexidine soap solution for uncomplicated carriage, in combination with two oral antibiotics for complicated carriage). Results: Six hundred and thirteen MRSA carriers were included, of whom 333 (54%) had complicated carriage; 327 of 530 patients (62%) with known complexity of carriage were treated according to the guideline with an absolute increase in treatment success of 20% (95% confidence interval 12%-28%). Among those with uncomplicated carriage, guideline adherence [adjusted odds ratio (OR(alpha)) 7.4 (1.7-31.7)], chronic pulmonary disease [OR(alpha) 44 (2.9-668)], throat carriage [OR(alpha) 2.9 (1.4-6.1)], perineal carriage [OR(alpha) 2.2 (1.1-4.4)] and carriage among household contacts [OR(alpha) 5.6 (1.2-26)] were associated with treatment failure. Among those with complicated carriage, guideline adherence was associated with treatment success [OR(alpha) 0.2 (0.1-0.3)], whereas throat carriage [OR(alpha) 4.4 (2.3-8.3)] and dependence in activities of daily living [OR(alpha) 3.6 (1.4-8.9)] were associated with failure. Conclusions: Guideline adherence, especially among those with complicated MRSA carriage, was associated with treatment success. Adding patients with extranasal carriage or dependence in daily self-care activities to the definition of complicated carriage, and treating them likewise, may further increase treatment success.