Somatic activating fibroblast growth factor 3 (FGFR3) mutations in human skin can cause seborrheic keratoses, one of the most frequent skin tumors in man. However, details of the involved mechanisms remain elusive. We analyzed 65 acanthotic seborrheic keratoses with varying vertical diameters for FGFR3 mutations using a SNaPshot multiplex assay. Immunohistochemistry was performed for Ki-67, bcl-2 and FGFR3 protein in all seborrheic keratoses and 19 normal skin samples. FGFR3 mutations were detected in 37 of 65 seborrheic keratoses (57%). These mutations were found both in flat (initial) and thick seborrheic keratoses. FGFR3 mutations were significantly associated with increased age and localization on the head and neck (P<0.01). Ki-67 expression was significantly higher in seborrheic keratoses than in normal epidermis independent of the FGFR3 status (P<0.001). Furthermore, FGFR3 mutations were associated with an increased expression of bcl-2 and FGFR3 protein (P<0.05). Our results indicate that FGFR3 mutations can occur early in the pathogenesis of at least a subset of seborrheic keratoses. Increased age appears to be a risk factor for these mutations. The preferential occurrence of FGFR3 mutations in seborrheic keratoses of the head and neck suggests a causative role for cumulative lifetime ultraviolet light exposure.