We evaluated the methylation status of p15 gene in a series of 65 patients with newly diagnosed acute promyelocytic leukemia (APL) receiving homogeneous treatment. Moreover, in 32 of them, the methylation status of p15 gene was correlated to the p15 m-RNA expression. In total, 31 patients had no p15 methylation (U group). An abnormal methylation pattern was found in 34 patients: in seven of these patients only methylated DNA was detected (M group), while in the remaining 27 patients (M/U group), both methylated and unmethylated DNA were amplified. Patients from M group showed a higher incidence of relapses and a lower disease-free survival (DSF) with respect to patients from U and M/U groups (29, 64 and 79% at 5 years for M, U/M and U patients, respectively, P=0.03), while p15 methylation had no impact on overall survival. The p15 expression was detectable in all patients with unmethylated DNA, in none of patients with fully methylated DNA and in 60% of patients with partially methylated DNA. The DFS estimate at 5 years for p15-negative patients was significantly lower than that of p15-positive patients (P=0.03). These data confirm that the presence of p15 methylation negatively influences the prognosis of APL, mainly when it represses the p15 gene transcription.