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Human immunodeficiency virus (HIV) infection is under global attention due to its rapid spread and high rate of morbidity and mortality. HIV gets an access into the mucosa of genital epithelium through binding to Langerhans cells. While viral load and CD4+ cell count are the main parameters to detect disease activity, new biomarkers are introduced as a potential parameter for monitoring of disease activity in HIV infected patients. Calcitonin Gene Related Peptide (CGRP) is a neuropeptide that is secreted by peripheral neurons at genital epithelia and plays an important role in limitation of HIV transmission and spread to infected CD4+ cells through its effect onto Langerhans cells. This study aimed to evaluate the serum level of CGRP in HIV infected patients and to determine whether CGRP can serve as an indicator of HIV infection activity. The study included 104 HIV patients and 24 normal controls. Patients were divided into four groups. Serum levels of CGRP were measured by ELISA and correlated to viral load and CD4+ cells count for patients in the four groups: primary HIV infection (PHI), chronic HIV infection (CHI) before combinational antiretroviral therapy (cART-naïve), chronic HIV infection after one year of cART-initiation, and chronic HIV infection after two years of cART. Serum levels of CGRP were also measured in sera of controls and compared to patients' groups. Serum levels of CGRP were significantly lower in cART naïve PHI and CHI patients in comparison with normal controls (p < 0.05), Also, serum CGRP levels were positively correlated with CD4+ cells count (p < 0.01), but negatively correlated with viral load (p>0.05). In conclusion, CGRP could be proposed as an indicator of disease activity in HIV patients., (Copyright© by the Egyptian Association of Immunologists.)