Autologous serum skin test (ASST) is mostly used in chronic spontaneous urticaria (CSU) to show autoreactivity. Interleukin-18 (IL-18) has also been shown to be involved in autoimmune conditions. To investigate the role of autoreactivity assessed by ASST in CSU and respiratory diseases and to investigate whether this autoreactive state is related to IL-18 level or other clinical covariates. Fifty-five patients with CSU (mean age: 40.3 +/- 12.3 years), 70 patients with persistent asthma (mean age: 43.7 +/- 9.6 years), 21 patients with seasonal allergic rhinitis (SAR) (mean age: 35.5 +/- 11.8 years) and 20 normal controls (mean age: 37.7 +/- 9.8) were included. All subjects underwent a laboratory examination and skin prick test. ASST was performed and serum IL-18 levels were measured in all subjects. Positive response to ASST and serum IL-18 levels were higher in CSU patients than those with respiratory diseases (asthma and SAR) (P = 0.034 and 0.002, respectively) and normal controls (P = 0.004 and 0.031, respectively). Considering all patients, IL-18 levels were higher in patients with positive ASST (301.8 +/- 194.4 vs. 241.8 +/- 206.3 pg/ml, P = 0.036) than ASST negative patients. ASST response was associated with disease severity in CSU (P = 0.037) and asthma patients (P = 0.001). Multivariate analysis showed that positive response to ASST was significantly associated with diagnosis of CSU (OR: 3.13, 95% CI: 1.25-7.87) and female gender (OR: 3.98, 95% CI: 1.19-13.38). ASST response could be related with activity of the disease. A positive ASST response found in respiratory diseases patients suggests that it may occur as a result of some inflammatory events during the diseases' process.