Chronic Spontaneous Urticaria (CSU) significantly affects quality of life. This study evaluates the efficacy of histaglobulin combined with antihistamine (bilastine) versus antihistamine alone in CSU management. A single-center, open-label, randomized trial was conducted in the dermatology OPD of a tertiary care hospital from September 2023 to August 2024. Fifty-seven eligible participants aged >
18 years with symptoms persisting >
6 weeks were randomized into test -histaglobulin plus bilastine group(n = 27) or bilastine alone (n = 30) groups. The test group received weekly histaglobulin injections and daily bilastine (20 mg), while the bilastine alone group received bilastine 20 mg only. Baseline data, including demographics, CSU characteristics, and Urticaria Activity Score (UAS), were recorded. Investigations included blood counts, renal/liver/thyroid function tests, serum IgE, absolute eosinophil count (AEC), vitamin B12 levels, and Autologous Serum Skin Test (ASST). UAS7 scores were recorded weekly for 6 weeks. The primary outcome was the change in UAS, with secondary outcomes assessing symptom control, and adverse events. A total 57 participants were recruited, with 27 and 30 in the test and bilastine alone group respectively. The combination of Histaglobulin with bilastine demonstrated significantly greater efficacy compared to bilastine alone. By Week 6, the Histaglobulin group achieved an 89.9% reduction in UAS versus 59.4% in the bilastine alone group (p <
0.01), with faster symptom resolution observed from Week 2. Laboratory findings showed notable reductions in serum IgE and AEC in the Histaglobulin group, suggesting enhanced modulation of allergic responses. No adverse effects were reported, highlighting the therapy's safety. The addition of Histaglobulin to bilastine provides a superior and well-tolerated treatment option for CSU, delivering faster symptom relief and better disease control. These findings support its use as an effective adjunctive therapy, warranting further investigation in larger sample size studies.