Summary The efficacy and safety of mupirocin calcium cream were compared with those of oral cephalexin in the treatment of secondarily infected eczema. In this multicentre, double-blind, double-dummy study, 159 patients with secondarily infected eczema (suitable for treatment with topical antimicrobials) and a total skin infection rating scale score of 8 or more were randomized to receive either topical mupirocin cream three times daily or oral cephalexin, 250 mg four times daily, for 10 days (intent-to-treat group). Clinical success (per-protocol group), defined in part as a patient with a response of improvement in the skin infection rating scale, was similar in the two groups: 89% for mupirocin (n = 44) and 82% for cephalexin (n = 38) [P = 0.29; 95% confidence interval (−8.4%, 22.5%)]. Bacteriological success (intent-to-treat group), defined as a patient with a response of eradication, improvement or colonization of bacteria at the end of therapy, however, was significantly higher for mupirocin [50% and 28% in the mupirocin (n = 48) and cephalexin (n = 47) groups, respectively; P = 0.005]. Mupirocin cream was as well tolerated as cephalexin; 9% and 13% of patients reported adverse events related or possibly related to study medication in the mupirocin and cephalexin groups, respectively. The most common adverse events overall were diarrhoea and nausea. Mupirocin cream applied three times daily is as effective clinically and superior bacteriologically compared with oral cephalexin given four times daily in the treatment of secondarily infected eczema of limited depth and severity. Mupirocin cream is as well tolerated as oral cephalexin, and more patients prefer the topical regimen, which should improve patient compliance.