The aberrant methylation of promoter CpG island is known to be a major inactivation mechanism of tumour-related genes. To determine the clinicopathological significance of gene promoter methylation in monoclonal gammopathies, we analysed the methylation status of 6 tumour suppressor genes and their association with loss of gene function. Methylation status of the genes p14, p15, p16, hMLH1, MGMT, and DAPK was determined by methylation-specific PCR in 52 cases: 30 MM, 13 MGUS, and 9 plasmacytomas, comparing them with their protein expression by immunohistochemistry, and association between methylation status, protein expression, and clinical characteristics was assessed. The methylation frequencies were 50% for p16, 17% for p15, 10% for hMLH1, 23% for MGMT and 30% for DAPK in MM samples, and 38%, 15%, 8%, and 15% for p16, p15, MGMT and DAPK respectively in MGUS samples. In plasmacytomas samples we found methylation of p16 in 55%, p15 in 22%, MGMT in 67% and DAPK in 44%. hMLH1 was unmethylated in all cases of MGUS and plasmacytomas. Immunohistochemistry showed that gene methylation was closely associated with a loss of protein expression. Our study demonstrates that methylation-mediated silencing is a frequent event in monoclonal gammopathies: 83% of MM, 46% of MGUS and 77% of plasmacytomas have at least one gene methylated, affecting different molecular pathways involved in cell cycle, DNA repair and apoptosis. This high prevalence of aberrant promoter hypermethylation suggests that monoclonal gammopathies carry a CpG island methylator phenotype, therefore the development of new DNA demethylation agents may be a potential therapeutic use in this disease.