Background: Chronic Spontaneous Urticaria (CSU) is a common health problem and its clear etiology is not established yet. Several theories have been tried to illustrate its etiology and pathogenesis. Autoantibodies and inflammatory cytokines like IL-23 and IL-17 are hypothesized to take part in CSU pathogenesis and outcome. Objectives: To detect serum levels of IL-23 and IL-17A among CSU patients and to determine its correlation with disease severity and its relation to autoreactivity. Methodology: Serum levels of IL-23 and IL-17A were measured in 23 patients with CSU (CSU group) and 23 healthy controls (control group). In CSU group, Weekly Urticaria Activity Score (UAS7) was recorded to assess disease severity. Autologous Serum Skin Test (ASST) was performed to assess autoreactivity. CSU patients᾿ group was subdivided, based on ASST, into positive ASST (ASST+) and negative ASST (ASST-) subgroups. Correlation of serum IL-23 & IL-17A levels, with UAS7 and ASST response were analyzed. Results: CSU group had higher serum IL-17A and IL-23 levels than control group (P=0.000). ASST+ CSU had higher serum IL-17A and IL-23 levels than ASST-ones (P=0.000). Additionally, UAS7 was higher in ASST+ subgroup than ASST- subgroup (32+11.7 versus 16.27+ 9.92; P =0.005). There was significant positive correlation between disease severity and serum levels of both IL-17A and IL-23 among CSU patients (r= 0.626 & P= 0.001 and r=0.515 & P= .012, respectively). Conclusion: Increased serum IL-17A and IL-23 levels may constitute two major determinants of CSU pathogenesis and severity.