Brain-derived neurotrophic factor (BDNF) signaling pathways have been shown to be essential for opioid-induced plasticity. We conducted an exploratory study to evaluate BDNF variability in opioid addict responders and nonresponders to methadone maintenance treatment (MMT). We analyzed 21 single nucleotide polymorphisms (SNPs) across the BDNF genomic region. Responders and nonresponders were classified by means of illicit opioid consumption detected in random urinalysis. Patients were assessed by a structured interview (Psychiatric Research Interview for Substance and Mental Disorders (PRISM)-DSM-IV) and personality was evaluated by the Cloninger’s Temperament and Character Inventory. No clinical, environmental and treatment characteristics were different between the groups, except for the Cooperativeness dimension (P < 0.001). Haplotype block analysis showed a low-frequency (2.7%) haplotype (13 SNPs) in block 1, which was more frequent in the nonresponder group than in the responder group (4/42 vs. 1/135; Pcorrected = 0.023). Fine mapping in block 1 allows us to identify a haplotype subset formed by only six SNPs (rs7127507, rs1967554, rs11030118, rs988748, rs2030324 and rs11030119) associated with differential response to MMT (global P sim = 0.011). Carriers of the CCGCCG haplotype had an increased risk of poorer response, even after adjusting for Cooperativeness score (OR = 20.25 95% CI 1.46–280.50, P = 0.025). These preliminary results might suggest the involvement of BDNF as a factor to be taken into account in the response to MMT independently of personality traits, environmental cues, methadone dosage and psychiatric comorbidity.