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Acne vulgaris is a distressing condition that affects the pilosebaceous follicles. Neuropeptides, notably substance P (SP), are considered to play a role in the pathophysiology of acne.To study the pilosebaceous units (PSUs) and the expression of SP and its receptor neurokinin-1 (NK-1R) in comedonal and inflammatory acne lesions in comparison with controls and to verify the relation of the expression of this neuropeptide and its receptor with stress.A total of 30 patients with acne vulgaris and 20 age-matched and sex-matched healthy controls were the participants of this study. Perceived Stress Scale was carried out for every patient. Skin biopsies were taken from comedonal lesions, inflammatory lesions, and normal control skin. Biopsies were subjected to routine hematoxylin and eosin staining for morphometric evaluation of PSUs and sebocytes as well as immunohistochemical staining for the detection of SP and NK-1R.Significantly larger PSUs and sebocytes were detected in acne lesions compared with the controls (P<0.0001). Both SP and NK-1R showed significantly higher expression in acne lesions compared with the controls (P<0.0001), being significantly higher in inflammatory lesions compared with comedonal lesions (P<0.0001). Both SP and NK-1R showed a significant direct correlation with Perceived Stress Scale in both comedonal and inflammatory lesions (P<0.05).SP and its receptor NK-1R seem to be important in the regulation of sebaceous gland function and provide a new insight into the involvement of the cutaneous nervous system in the pathogenesis of acne.