Activating FGFR3 mutations have been identified in a variety of benign skin lesions (seborrheic keratosis, epidermal nevus, solar lentigo). However, the functional consequences of these mutations in the human epidermis are unknown. We therefore analyzed functional effects of the common R248C mutation in HaCaT keratinocytes. The cells were stably transduced with the R248C FGFR3 mutation or FGFR3-IIIb wildtype sequence using a retroviral system. The R248C mutant keratinocytes revealed significantly enhanced cell growth compared with wildtype cells after reaching confluence. Likewise, apoptosis and attachment to fibronectin were significantly reduced in mutant cells. In contrast, there was no difference regarding migration and oncogene-induced senescence. Gene expression analysis revealed only a few differentially expressed genes between mutant and wildtype HaCaT keratinocytes. ERK1/2 appear to be involved in the FGFR3-dependent signalling of R248C mutant keratinocytes. Our results indicate that an increased cell number at confluence along with reduced apoptosis may contribute to the growth of benign acanthotic tumors in the human epidermis.