Background: Post-dural puncture headache is a common complication of spinal anesthesia mostly in parturient. The aim of this study is to evaluate and compare the effect of ondansetron and aminophylline on PDPH. Methods: In this study we administered (1 mg/kg) of aminophylline in group A, (0.15 mg/kg) of ondansetron in group B and 5 cc of normal saline as placebo in control group. Blood pressure and heart rates were monitored since entrance of the patient to the operating room till the end of stay in recovery room and any significant changes were documented. Afterwards, PDPH and post-operative nausea and vomiting were followed during 24, 48 and 72 h periods since the performance of spinal anesthesia by calling each patient and the severity of headache was noted by numerical rating scale which had been already explained to the patients. Results: Although there was no difference in the incidence of PDPH among three group cases (p=0.89), the severity of the headache was significantly lower in the ondansetron group (NRS: 4.82) comparing to aminophylline (NRS: 7.71) and control (NRS: 6.65) groups (P<0.001). Moreover, the data showed that significant hypotension occurring during operating time, results in twice as much PDPH afterwards (p=0.009). Conclusion: This study shows that although (0.15 mg/kg) ondansetron does not reduce the incidence of PDPH, it significantly reduces the severity of headache also shows that aminophylline has no effect on reduction of incidence nor severity of PDPH.