Background: Low testosterone levels are frequently found in male patients with critical illness. The underlying mechanisms are not exactly known. More knowledge of the pathophysiology is needed before considering replacement therapy. Methods: Observational pilot study to assess the changes in androgen metabolism in male patients with sepsis who require mechanical ventilation. Gonadal hormone levels and their steroid precursors were measured during the first week of mechanical ventilation. Results: Mechanical ventilation in male patients with sepsis was associated with very low testosterone levels, markedly elevated serum oestradiol levels, and inappropriately low luteinising hormone and follicle-stimulating hormone levels. During the first week of mechanical ventilation oestradiol levels gradually decreased, whereas testosterone levels remained low. Precursor steroids such as high-density lipoprotein cholesterol and dehydroepiandrosterone were reduced whereas the androstenedione concentration was maintained within the high-normal range. Conclusion: Sepsis in male patients on mechanical ventilation is associated with very low testosterone and markedly elevated oestradiol levels, caused by a combination of reduced gonadotropin secretion, reduced androgen precursor availability and increased aromatisation. The impact of hypotestosteronaemia on recovery from critical illness needs further study. © 2020, Netherlands Society of Intensive Care. All rights reserved.