The use of all-trans retinoic acid (ATRA) has markedly improved the survival of patients with acute promyelocytic leukemia (APL), making it potentially curable. However, the identification of prognostic markers predictive of durable remission remains an important aspect in risk-adjusted treatment algorithms. High presentation leucocyte count has been found to correlate with inferior disease-free-survival (DFS). However, recent studies have also shown aberrant promoter methylation of the CDKN2B (alias p15) gene to be a negative prognostic factor. Promoter methylation results in the formation of a repressor complex, leading to chromatin compaction and suppression of gene expression and is, therefore, an alternative mechanism of gene inactivation. CDKN2B, a cyclin-dependent kinase inhibitor, is a tumor suppressor gene inhibiting cell cycle progression. The CpG island inside the CDKN2B promoter is hyper-methylated in approximately 50 - 60% of APL patients. CDKN2B methylation correlates negatively with DFS. As methylation-induced inactivation of CDKN2B pre-disposes to unchecked cellular proliferation, CDKN2B hyper-methylation is also associated with high presentation leucocyte count. Multivariate analysis in several studies, however, has shown that the negative prognostic impact of CDKN2B methylation is independent of its association with high leucocyte counts. Therefore, CDKN2B methylation is a potential prognostic factor that may be incorporated into a risk-stratified therapeutic strategy, which aims at achieving a cure with optimal amounts of treatment.