Background The aim of the current study was to investigate the effect of administration of cosyntropin after accidental dural puncture (ADP) on the incidence of postdural puncture headache (PDPH) and the need for therapeutic epidural blood patch (EBP). Methods Ninety parturients who suffered an ADP were studied. After delivery, patients were randomly assigned to one of two equal-sized groups. In group I (cosyntropin group), patients received cosyntropin in a dose of 1 mg intravenously. In group II (control group), patients received an equal volume of normal saline. Results Fifteen patients (33%) in the cosyntropin group suffered from PDPH, compared with 31 patients (68.9%) in the control group (P = 0.001). Significantly fewer patients in the cosyntropin group required an EBP, compared with the control group (5 patients [11.1%] vs. 13 patients [28.9%], respectively; P = 0.035). The Kaplan-Meier curves for the occurrence of PDPH showed a hazard ratio of 0.32 (95% CI = 0.16-0.55, P < 0.0001). The time from ADP to occurrence of PDPH was significantly longer in the cosyntropin group (27.2 [7.7] h) in comparison with the control group (17.5 [4.9] h; P < 0.001). However, there were no statistically significant differences among patients who developed PDPH in both groups with regard to the severity or duration of PDPH or with regard to the need for EBP or for repeat EBP (P > 0.05). Conclusions Administration of cosyntropin after ADP in parturients was associated with significant reduction in the incidence of PDPH and need for EBP and significant prolongation of the time from ADP to occurrence of PDPH.