The relationship between topical corticosteroid use, potency, treatment duration, concomitant exposure to systemic corticosteroids, and risk of diabetes has been incompletely studied. To investigate an association between intense, longstanding topial corticosteroid use and diabetes mellitus. Data for this nested case-control study were obtained from the PHARMO Record Linkage System, including linked drug dispensing and hospital records of >2.5 million individuals in defined areas of the Netherlands. Users of topical corticosteroids during 1992-2004, without diabetes, with >/=2 topical corticosteroid dispensings and >/=4 years of follow-up were selected. Diabetes onset was defined as first occurrence (index date) of an antidiabetic drug dispensingor hospitalization for diabetes. Cases were matched 1 :::: 4 by age and sex to controls, with >/=2 topical corticosteroid dispensings and similar follow-up duration. Use of topical corticosteroids and systemic corticosteroids and/or inhaled corticosteroids as co-medication was classified as current, recent and past/never (=2 years, 2-4 years and >4 years ago, respectively). Multivariate regression analyses were adjusted for co-medication and co-morbidity. Among 192 893 incident topical corticosteroidusers, 2212 developed diabetes and could be matched to 8582 controls. Current topical corticosteroid use was associated with an (unadjusted) 1.24-fold increased risk of diabetes (unadjusted OR 1.24; 95% CI 1.11, 1.40). The odds ratio increased to 1.32 with >180 days of topical corticosteroid use (95% CI 1.14, 1.54) and to 1.44 with a cumulative topical corticosteroid load (combined potency and amount) of 731-1460 mg (95% CI 1.21, 1.72). Among past/never users of systemic corticosteroids and/or inhaledcorticosteroids, current use of topical corticosteroids remained associated with a 1.27-fold increased diabetes risk (unadjusted OR 1.27; 95% CI 1.10, 1.47) compared with past users of topical corticosteroids. An increased risk of new-onset diabetes maybe an important consideration in the treatment of patients with topical corticosteroids, especially when intense skin treatment is needed. Future studies are needed to endorse these findings in other populations.