Aberrant methylation of tumor suppressor genes (TSG) has been studied in multiple myeloma (MM). We determined the methylation status of the FHIT (fragile histidine triad) gene, a putative TSG, in 48 patients with MM. Clinical association with its methylation status was then analyzed. The FHIT gene methylation was observed in 21 of the 48 patients (44%). No association between FHIT gene methylation and clinical variables such as age, gender and clinical stage was found. However, the estimated 50% survival time of the methylated group was significantly shorter than that of the unmethylated group (18.2 vs. 45.1 months, P < 0.05). Univariate analysis revealed adverse prognostic factors: FHIT gene methylation (P = 0.028), poor performance status (I to IV, P = 0.002), anemia (< or =8.5 g/dL, P = 0.007), hypoalbuminemia (< or =3.5 g/dL, P < 0.002), high serum C-reactive protein levels (>0.5 mg/dL, P = 0.002), elevated beta-2-microglobulin serum levels (>6.5 mg/L, P < 0.001), and treatments not including autologous peripheral blood stem cell transplantation (auto-PBSCT) (P = 0.007). Multivariate analysis identified FHIT gene methylation [hazard ratio (HR) 1.722, 95% confidence interval (CI) 1.150-2.603, P = 0.009], elevated beta-2-microglobulin serum levels (>6.5 mg/L, HR 2.005, 95% CI 1.035-3.937, P = 0.004), and treatments not including auto-PBSCT are independent predictive variables. These findings indicate that aberrant methylation of the FHIT gene is an independent adverse prognostic factor in MM.