Treating chronic urticaria (CU) that is unresponsive to H1-antihistamines (H1AHs) is challenging, and the real-world effectiveness of omalizumab remains unclear. Our aim was to evaluate the real-world effectiveness of omalizumab, optimal response assessment timing, and predictive factors. Initially, 5535 patients with CU who were receiving at least 20 mg of loratadine daily for at least 6 months (January 2007-August 2021) were screened. Ultimately, 386 patients who had been receiving omalizumab add-on treatment for >6 months were followed-up for more than 2 years. Predictors of treatment response to omalizumab add-on therapy for patients with antihistamine-refractory CU were identified by using a generalized linear model. In our retrospective cohort, omalizumab treatment showed cumulative response rates of 55.2% at 3 months, 71.0% at 6 months, and 81.4% at 9 months for patients with H1AH-refractory CU. Analysis of longitudinal responses to omalizumab treatment revealed 3 distinct clusters: favorable (cluster 1 [n = 158]), intermediate (cluster 2 [n =1 43]), and poor responses (cluster 3 [n = 85]). Subjects were categorized on the basis of whether they had achieved a complete response within 3 months; 213 early responders, 117 late responders, and 56 nonresponders were identified. The initial dose of omalizumab differed significantly among the 3 clusters. Low total IgE level (<40 kU/L) predicted nonresponse (odds ratio [OR] = 3.10 [P = .018]). Early responders were associated with a higher initial omalizumab dose (≥300 mg) (OR = 2.07 [P = .016]), higher basophil counts (OR = 2.0 [P = .014]), total IgE levels exceeding 798 kU/L (OR = 0.37 [P = .047]), and lower platelet-to-lymphocyte ratio (OR = 0.50 [P = .050]). Real-world data reveal 3 distinct clusters for response to omalizumab treatment; confirm low serum total IgE level (<40 kU/L) as a predictor of nonresponse; and identify potential biomarkers, including IgE level, basophil count, and PLR, for early responders.