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Substance P (SP) is a neurotransmitter emitted from neurons that plays a role in the pathogenesis of itching conditions including chronic urticarial (CU). The present research aims to investigate the serum level of S.P among CU patients and compare them with healthy subjects and explore how it correlates with the severity of urticaria. The present research was conducted on 87 CU patients who visited the allergy clinic of Ghaem Hospital, Mashhad, Iran from October 2017 to June 2018. Besides, 86 healthy subjects were recruited as the control group. Background information of patient was collected including age, sex, duration of the disease and the co-occurrence of angioedema. S.P serum level was measured in two groups by ELISA method. In the patients group, the autologous serum skin test (ASST) was performed along with the urticaria evaluation questionnaire include Urticaria Activity Score 7 (UAS7), Urticaria Control Test (UCT) and Chronic Urticaria Quality of Life (CU-Q2OL). Among the patients, the SP serum level showed to be about two times higher than the healthy subjects (p˂0.001). SP showed to be increased as patients' age grew (p=0.010). In patients with a positive ASST, SP level was higher (p=0.012). No correlation was found between SP and the presence of angioedema among patients. There was no correlation between the SP serum level and the scores obtained from urticaria evaluation questionnaires. SP among CU patients was higher than healthy subjects. SP was also higher among female, older and positive ASST patients. The SP value was not correlated with the severity of urticaria, angioedema. In conclusion, Using SP antagonist drugs could be a potential treatment for chronic urticaria. [ABSTRACT FROM AUTHOR]