OBJECTIVE No evidence-based guideline has been approved for the postoperative management of pediatric patients with tethered cord syndrome (TCS). The purpose of this randomized clinical trial was to evaluate the effectiveness of prone positioning and acetazolamide administration on complication rates following spinal cord untethering surgeries. METHODS From October 2012 to February 2015, patients with a primary diagnosis of TCS who were admitted to the Children's Medical Center Hospital of Iran were randomly allocated to 1 of 4 intervention modality groups postoperatively: 1) Group A, acetazolamide administration for 10 days; 2) Group B, prone positioning for 10 days; 3) Group C, acetazolamide administration and prone positioning for 10 days; and 4) Group D, no intervention. CSF leakage, CSF collection, wound dehiscence, operative site infection, and secondary surgical wound repair were considered failure. RESULTS A total of 161 patients were enrolled in this study (Group A, n = 39 [24.2%]; Group B, n = 41 [25.5%]; Group C, n = 39 [24.2%]; and Group D, n = 42 [26.1%]). The overall failure rate was 12.42% (20 patients). Complication rates through pooled analyses were as follows: CSF leakage (n = 9, 5.6%), CSF collection (n = 12, 7.5%), wound dehiscence (n = 2, 1.2%), and infection of operation site (n = 3, 1.9%). Two patients (1.2%) required surgical secondary wound repair due to complications. CSF leakage and collection rates were significantly lower in patients who underwent prone positioning (p = 0.042 and 0.036, respectively). The administration of acetazolamide, either isolated or in combination with prone positioning, not only could not significantly lower the complication rates, but also added the burden of side effects. CONCLUSIONS The current study demonstrates the possible role of prone positioning in mitigating the complication rates subsequent to untethering surgeries. Clinical trial registration no.: NCT01867268 (clinicaltrials.gov)