Mast cells and basophils interact with various cells in the urticaria lesion microenvironment, such as macrophages,.which form an essential component of innate immunity, and are involved in numerous functions including protein secretion. Objective: The aim of the present study was to characterize the macrophage phenotype in urticarial lesions of patients with chronic spontaneous urticaria (CSU) nonresponsive to antihistamines at optimized doses. And compare the phenotype with clinical and laboratory parameters such as age, gender, urticaria time, C-reactive protein (CRP), and total serum IgE, and autologous serum skin test (ASST). Methods: Twenty-eight patients with CSU refractory to antihistamines were included in the study. Epidemiological data, C-reactive protein, D-dimers, basophils in peripheral blood, and total serum IgE and ASST were assessed. The mannose receptor (CD206), CD163, CMAF, and pSTAT 1 were used to characterize the M1/M2 macrophage subpopulations. The immunolabeled cells per square millimeter were manually enumerated at a 400× magnification in 12 optical fields via light microscopy. Results: A predominance of M2 macrophages was seen in CSU patients. Statistical differences were observed between the CD206 marker and the disease course. No correlation was found between biomarkers and macrophage populations. Expression of CMAF was significantly higher in the patient sample compared to that in the control skin (patients without history of urticaria; p-value < 0.001). Conclusion: M2 macrophages were seen with significantly higher CMAF expression, which indicates macrophage activation in patients with CSU. CD206 expression was inversely correlated with disease time.