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Background: A retrospective study has shown lesser days of hospital stay in patients with increased levels of intra-operative end-tidal carbon dioxide (ETCO 2 ). It is probable that hypercapnia may exert its beneficial effects on patients′ outcome through optimization of global hemodynamic and tissue oxygenation, leading to a lower rate of post-operative complications. This study was designed to test the hypothesis that higher values of intra-operative ETCO 2 decrease the rate of post-operative complications. Materials and Methods: In this randomized, double-blind clinical trial, 78 adult patients scheduled for percutaneous nephrolithotomy (PCNL) were prospectively enrolled and randomly divided into three groups. ETCO 2 was set and maintained throughout the procedure at 31-33, 37-39 and 43-45 mmHg in the hypocapnia, normocapnia and hypercapnia groups, respectively. The rates of post-operative complications were compared among the three groups. Results: Seventy-five patients completed the study (52 male and 23 female). Ten (38.5%), four (16%) and two (8.3%) patients developed post-operative vomiting in the hypocapnia, normocapnia and hypercapnia groups, respectively (P = 0.025). The nausea score was significantly lower in the hypercapnic group compared with the other groups (3.9 ± 1.8, 3.2 ± 2.1 and 1.3 ± 1.8 in the hypocapnia, normocapnia and hypercapnia groups, respectively; P = 0.000). Time to return of spontaneous respiration and awakening were significantly decreased in the hypercapnia group compared with the other groups (P < 0.01). Conclusion: Mild intra-operative hypercapnia has a protecting effect against the development of post-operative nausea and vomiting and decreases the duration of emergence and recovery from general anesthesia.