Background: Nonsedating antihistamines are the treatment of choice for chronic spontaneous urticaria (CSU), while omalizumab and immunosuppressants have also been approved as an add-on treatment. Autologous whole-blood injection (AWBI) has been used in previous studies with ambiguous results. The aim of our study was to evaluate changes in the Urticaria Activity Score (UAS7), Dermatology Life Quality Index (DLQI), and Chronic Urticaria Quality of Life (CU-Q2oL) score, and also the association of serologic markers with disease severity measures after AWBI. Methods: In this observational study, AWBIs were performed (8 courses on a weekly basis) in adults with refractory CSU, who refused an add-on treatment with either omalizumab or immunosuppressants. UAS7, DLQI, and CU-Q2oL questionnaires and serum concentrations of total IgE, C-reactive protein (CRP), and D-dimer were evaluated before and after the intervention. Results: Nineteen patients (12 females; mean age 54 ± 20.8 years) completed the protocol. Following AWBI, significant improvements in the UAS7 (34.26 ± 8.04 vs. 12.52 ± 10.83, p < 0.001), DLQI (11.63 ± 5.51 vs. 3.47 ± 2.85, p < 0.001), and CU-Q2oL score (32.97 ± 18.71 vs. 10.94 ± 7.71, p < 0.001) were recorded. A negative correlation between the baseline D-dimer levels and UAS7 and DLQI variations (p = 0.002 and p = 0.001, respectively) was noted. D-dimer levels ≥292 ng/mL have been associated with poor responsiveness (sensitivity 75%; specificity 83.3%). No correlation with either total immunoglobulin E or CRP levels was observed. Conclusion: AWBI appears to be a safe, alternative, add-on therapeutic option in refractory CSU, particularly in patients with low plasma levels of D-dimer.

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