The influence of sex on prevalence and presentation of human depression necessitates studying its role in depression. Additionally, stress can also affect the incidence and progression of depressive phenotypes. Hypothalamus is a well-reported sexually dimorphic brain region. Hence, we performed a gene-array to uncover the chronic stress-induced transcriptional changes in the hypothalamus of male, intact female (with ovaries) and ovariectomized female mice. Chronic variable mild stress model was used to induce depression-like behavior in mice, assessed by despair behavior in forced swim test. We observed 90, 205 and 106 uniquely expressed genes among the 114, 226 and 121 stress-regulated genes (fold change > 1.2 and p < 0.05) in male, intact female, and ovariectomized female group mice respectively. Pathway analysis of the altered genes identified 'posttranslational processing of neuroendocrine peptides' as the most significantly enriched pathway and also differentially regulated among the groups. Arginine vasopressin and Cholecystokinin were upregulated in males whereas in ovariectomized females Arginine vasopressin alone was upregulated, and Oxytocin was downregulated in intact females. A greater number of nodes and connections found in intact females indicate their intricate molecular response to chronic stress condition. These results suggest that stress-regulated transcriptional changes in the hypothalamus are sex-specific and ovarian hormone-dependent, which warrants urgent sex-based medical attention in depressive disorder. (C) 2017 Published by Elsevier Inc.