Abstract Background Calcitonin gene-related peptide monoclonal antibodies (CGRP mAbs) are an effective preventative therapy for migraine; however, there have been rare reports of possible inflammatory complications. The primary objective of this study was to examine the impact of CGRP mAbs on immune system activation by evaluating the plasma cytokine profile of a cohort of patients pre- and post-CGRP mAb. Methodology A prospective cohort study was undertaken at a tertiary headache service. Following informed consent and screening, the plasma cytokine profile of participants was determined using a Simoa CorPlex human cytokine 10-plex with ten targets: interferon gamma, interleukin-1β, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-22, and TNF⍺ prior to initiation of CGRP mAb and following 3 months of therapy. A comparator group of healthy controls at a single time point was also included. Results A total of 22 patients with chronic migraine and 10 healthy controls were included in the study. Administration of CGRP mAb was not associated with a significant change in cytokine expression (Wilk’s lambda 0.528, p  = 0.448). On post-hoc analysis, there was a significant reduction in IL-5 levels ( z  = − 2.321, p  = 0.020) following CGRP mAb therapy. Conclusion In this study of patients with chronic migraine, we found no evidence that treatment with CGRP mABs is associated with a significant alteration in plasma cytokine levels or shift to a Th1 phenotype.