Calpain, also named CAPN (for calcium-activated neutral protease), is a ubiquitous intracellular cytoplasmic non-lysosomal cysteine endopeptidase that requires calcium ions to exert its activity. Two major isoenzymes are known—µ-calpain (CAPN1) and m-calpain (CAPN2)—requiring micromolar and millimolar calcium concentrations for activation, respectively. Many known substrates of the different calpain isoenzymes, such as the transcription factors c-Fos and c-Jun, the tumour suppressor protein p53, protein kinase C, pp60src, or the adhesion molecule integrin, have been implicated in the pathogenesis of various malignancies including squamous (SCC) and basal (BCC) cell carcinomas of human skin, suggesting an important role of the calpain isoenzymes in malignant diseases. We have analysed the expression of CAP1 and CAPN2 protein and mRNA expression in BCCs and SCCs of human skin. Interestingly, CAPN1 immunoreactivity (streptavidin–peroxidase technique) was markedly reduced in BCCs compared to normal human skin or SCCs, while in contrast CAPN1 mRNA levels (determined by real-time PCR) were markedly elevated in BCCs and SCCs compared to normal human skin. No differences were found analysing CAPN2 protein and mRNA expression in normal human skin, BCCs and SCCs. In conclusion, we have demonstrated for the first time alterations in calpain mRNA expression and protein content in malignant skin tumours that may be of importance for the tumorigenesis and growth characteristics of BCCs and SCCs. However, our results do not allow conclusions on the function of CAPN1 and CAPN2 in BCCs and SCCs. It is not known if the CAPN genes in BCCs or SCCs exhibit functionally inactivating mutations or whether decreased CAPN1 protein expression in BCCs and elevated CAPN1 mRNA in BCCs and SCCs reflect a feedback loop coupled with increased degradation or proteolysis of CAPN1 protein. Copyright © 2003 John Wiley & Sons, Ltd.