Background Obesity-related dysregulation of leptin signaling (e.g., hyperleptinemia due to central functional resistance) may affect mood. However, evidence for leptin dysregulation in major depressive disorder (MDD) is conflicting. Inconclusive findings may be attributable to heterogeneity of MDD, aggregating biologically different subtypes. We examined the relationship of leptin with MDD, its common subtypes (typical and atypical), and clinical features. Methods The sample consisted of participants (aged 18 to 65 years) from the Netherlands Study of Depression and Anxiety with current (n = 1062) or remitted (n = 711) MDD and healthy control subjects (n = 497). Diagnoses of MDD and subtypes were based on DSM-IV symptoms. Additional symptoms were measured with the Inventory of Depressive Symptomatology. Blood levels of leptin and adiposity indexes (body mass index and waist circumference) were assessed. Results As compared to control subjects, higher leptin was associated with the atypical MDD subtype both for remitted (n = 144, odds ratio = 1.53, 95% confidence interval = 1.16–2.03, p =.003) and current (n = 270, odds ratio = 1.90, 95% confidence interval = 1.51–2.93, p = 5.3e-8) cases. This association was stronger for increasing adiposity levels (leptin by body mass index interaction, p <.02), strengthening the hypothesis of the involvement of leptin resistance. No association with leptin was found for overall MDD or the typical subtype. Among currently depressed patients, higher leptin was associated with key symptoms identifying the atypical subtype, such as hyperphagia, increased weight, and leaden paralysis. Conclusions Leptin dysregulation (resistance) may represent an underlying mechanism connecting obesity and MDD with atypical features. Development of treatment effectively targeting leptin resistance may benefit patients with atypical depression characterized by obesity-related metabolic alterations.