- Chronic idiopathic (spontaneous) urticaria (CIU) is sometimes resistant to the conventional and high doses of antihistamines (AHs). This study compares the clinical and laboratory characteristics of AH responsive and AH-resistant CIU subjects. Clinical and laboratory data were retrospectively collected from 385 CIU patients. Urticaria activity score (UAS), concomitant angioedema, dermatographism, positive autologous serum skin (ASST), and laboratory data were collected. The control group consisted of 44 sex- and age-matched healthy individuals. Two hundred forty-five CIU patients controlled with AH medications were included in the CIU group. Forty-six patients failed to show clinical improvement during 8 weeks of treatment with fourfold AH doses and were included in the resistant CIU (R-CIU) group. The R-CIU group was characterized with a higher incidence (58.7%) of angioedema than the CIU group (28.5%; p < 0.001), more cases concomitant physical urticaria (23.9% in R-CIU versus 12.2% in CIU; p = 0.014), more positive ASST (73.9% in R-CIU versus 45.4% in CIU; p < 0.001), and higher baseline UAS (5.28 ± 0.81 in R-CIU versus 3.32 ± 1.25 in CIU; <0.001). R-CIU was characterized with more severe basopenia (0.04 ± 0.07 cell/mm(3) versus 0.16 ± 0.13 cell/mm(3); p < 0.001), higher mean platelet volume (10.87 ± 2.21 femtoliter (fl) versus 8.65 ± 1.74 fl; p < 0.001), higher levels of C-reactive protein (8.62 ± 3.91 mg/L versus 2.49 ± 1.34 mg/L; <0.001), and higher levels of serum C3 (1.66 ± 0.36 g/L versus 1.19 ± 0.35 g/L; p < 0.001. R-CIU is a clinically more severe disease with laboratory features of low-grade inflammation and platelet activation.