Concentrations of pharmaceutical pollutants are usually very low in polluted waters and traditional separating methods are not enough efficient for their separation and detection. Regarding the daily increasing consumption of resistant and dangerous antibiotics and their wide spread polution proliferation, effort for development of new methods and technologies for their separation and detection is highly important. In recent years, solid phase extraction (SPE) because of its wide applications in various fields of science and technology including chemistry, pharmacy, nutrition, hygiene, environment, agriculture, forensics, biology, and toxicology has attracted more attention. Since solid phase extraction is an appropriate method to detect pollutants in low concentrations, in this research, SPE is used for separation and detection of two cephalosporin antibioticsfrom artificial and intact municipal wastewater samples. Cephalosporin antibiotics are among the most common antibiotics used for treatment of a large number of infectious diseases. Therefore, separation and detection of the previously mentioned drugs as new-found pollutants is essential. In this study, the solid phase extraction method was used to separate cefuroxime and ceftazidime from artificial wastewater. The experiments were carried out using a syringe pump and C18 column. During the extraction steps, solvent and sample were passed through the column at a specified flow rate. The target analyte was collected and condensed after elution by solvent. The extracted samples were injected to HPLC. Methanol was used as the mobile phase) A (and 0.1 molar formic acid in deionized water was used as the mobile phase (B), such that A/B = 40/60 v/v. Analyses were carried out at a flow rate of 0.8 ml/min. The Uv-Vis detector wavelength was set at 260 nm to improve the accuracy of the method. Column temperature was kept at ambient temperature. The effect of three parameters pH, flow rate and elution volume were investigated. In order to study the effect of these parameters, experiments were designed by Minitab 17 software and RSM method, and data analyses were done by ANOVA. The obtained model by RSM method for extraction concentration is quadratic. The R 2 coefficient for the obtained model for extraction concentration of ceftazidime and cefuroxime is 96.7 % and 97.7 %, respectively. The optimal value of extraction concentration of ceftazidime and cefuroxime was 99.5 % and 81.9 %, respectively. These optimal parameters values correspond to a pH value of 2, a flow rate of 2 ml/min, and an elution volume of 4 ml. The limit of detection (LOD) for ceftazidime and cefuroxime is 5.2 and 9.6 mg/L, respectively. The limit of detection of SPE method for the above mentioned antibiotics was compared with other methods reported in the literature. The results indicate that this SPE method is is superior for Ceftazidime. The elution solvent was assessed under optimal conditions and methanol demonstrated the best performance for these antibiotics. The best time for drying the SPE column was 45 minutes after elution. Key Words Solid phase extraction, Cephalosporin antibiotics, Separation, Pharmaceuticals,