Acute promyelocytic leukaemia (APL) has distinct clinicopathological and molecular features. However, the profile of aberrant gene promoter methylation is undefined. In this study, methylation-specific polymerase chain reaction (MSP) was used to define the methylation status of a panel of nine genes, comprising p15, p16, RARbeta, oestrogen receptor (ER), E-cadherin (E-CAD), p73, caspase 8 (CASP8), VHL and MGMT, in 29 patients with APL. Aberrant methylation of p15, ER, RARbeta, p16 and E-CAD occurred, respectively, in 23 (79%), 14 (48%), six (21%), six (21%) and two (7%) patients at diagnosis, but p73, VHL, CASP8 and MGMT were not methylated in any patients. There was methylation of one gene in 13 patients (45%), two genes in four patients (14%), three genes in six patients (21%) and four genes in three patients (10%). Concurrent methylation of two or more genes occurred in 13 patients (45%). No association was identified between gene methylation and presenting clinicopathological features. However, p15 methylation was significantly associated with an inferior disease-free survival (DFS, P = 0.008), and remained the only poor prognostic factor in multivariate analysis (P = 0.019). In APL, p15, p16, ER and RARbeta were most frequently methylated. This profile is distinct from other types of myeloid leukaemias. p15 methylation has a poor prognostic impact on DFS.