Impaired regulation of the hypothalamic-pituitary-adrenal (HPA) axis is substantially involved in several psychiatric disorders. Smoking interferes with HPA axis by activating proopiomelanocortin (POMC) neurons and thus stimulating the expression of POMC. The POMC transcript is processed into several peptide hormones, such as adrenocorticotropic hormone (ACTH) and alpha-melanocyte-stimulating hormone (alpha-MSH), that play a role in stress response and weight control. In alcohol dependence, POMC promoter methylation is associated with craving. Here, we describe evidence of altered POMC promoter methylation in smoking. To determine how tobacco dependence and its withdrawal affect POMC promoter-specific DNA methylation, we assessed blood samples of 36 tobacco dependent individuals at day 1, 7 and 14 of withdrawal compared to 41 healthy controls using direct bisulfite sequencing. We found that POMC promoter methylation is significantly higher in smokers than in non-smokers. Moreover, this methylation difference does not readapt within 14 days of abstinence. We offer two explanatory models: Smokers could have a higher methylation state before the onset of smoking and this premorbid status might be acquired by environmental factors in early life. Alternatively, smoking may activate POMC neurons and its protein expression. Therefore, increasing methylation status of its promoter might be an adjustment to keep homeostasis. In either way, altered POMC methylation in smokers seems to indicate an adaptation of stress signaling, thereby potentially serving as a marker for stress-related functions that support the addiction.