Neurofibromatosis type 1 (NF1) is a common autosomal dominantly inherited disorder characterized by neurofibromas and café-au-lait macules. Most of the NF1 gene germline mutations result in a reduction in the level of neurofibromin. As shown recently, the neurofibromin level can be regulated posttranslationally through alteration of the protein half-life. This raises the question as to whether this type of regulation is also operating in cultured melanocytes of NF1 patients especially in melanocytes derived from café-au-lait macules. In melanocytes cultured without phorbol 12-myristate 13-acetate (PMA) the neurofibromin half-lives were 24 h (healthy controls, MC), 26 h (apparently healthy skin of NF1 patients, MNFS) and 25 h (café-au-lait macules of NF1 patients, MNFC). In PMA-stimulated cells the neurofibromin half-lives were 68 h (MC) and 73 h (MNFS) whereas it was 45 h in melanocytes derived from NF1 café-au-lait macules. The amount of NF1 mRNA was not altered under these culture conditions as shown by competitive RT-PCR. We speculate that this regulation is involved in the formation of some NF1 symptoms, for instance in the formation of café-au-lait macules.