BIK (bcl2-interacting killer) is the founding member of the BH3-only bcl-2 family of pro-apoptotic proteins, which is suppressed in various cancers. In multiple myeloma (MM), BIK has been shown to be epigenetically silenced in vitro, but there is a lack of clinical data. We investigated the CpG methylation status of the BIK promoter in a well-characterized clinical series of patients with MM and investigated its clinical relevance. Forty patients with MM (21 male, 19 female; mean age 66) were studied. According to the International Staging System (ISS) they were classified as 16 patients with stage I, 12 patients with stage II and 12 patients with stage III disease. Methylation in the BIK CpG island was assessed by methylation-specific polymerase chain reaction (MSP) assay. Logistic regression analysis was used to investigate associations between gene methylation and age, ISS stage, performance status, extramedullary disease, bone disease, anemia (hemoglobin ≤10 mg/dL), serum albumin, β(2)-microglobulin level and relapsed/refractory disease. Methylation in the BIK CpG island was detected in 16 patients (40%), with a trend favoring male gender (odds ratio [OR] = 3.08, p = 0.09) and development of bone disease and extramedullary disease (OR = 1.6, p = 0.35 and OR = 3, p = 0.14, respectively). Patients with MM with methylated BIK CpG island had a statistically significant risk for disease evolution to relapsed/refractory disease (OR = 5.4, p = 0.03). This study provides clinical evidence that methylation-induced transcriptional silencing of the BIK pro-apoptotic gene may occur in MM, which might serve as a predictor of the development of relapsed/refractory MM. These findings warrant validation in larger cohorts of patients and suggest therapeutic utility for agents that enhance BIK expression.