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Background The purpose of the study was to compare the effect of using volume-controlled ventilation (VCV) versus pressure-controlled ventilation (PCV) on blood loss in patients undergoing posterior lumbar inter-body fusion (PLIF) surgery. Methods In a randomized, single-blinded, parallel design, 78 patients, candidates for PLIF surgery, were randomly allocated into two groups of 39 to be mechanically ventilated using VCV or PCV mode. All the patients were operated in prone position by one surgeon. Amount of intraoperative surgical bleeding, transfusion requirement, surgeon satisfaction, hemodynamic parameters, heart rate, and blood pressure were measured as outcomes. Results PCV group showed slightly better outcomes than VCV group in terms of mean blood loss (431 cc vs. 465 cc), transfusion requirement (0.40 vs. 0.43 unit), and surgeon satisfaction (82.1% vs. 74.4%); however, the differences were not statistically significant. Diastolic blood pressure 90 and 105 min after induction were significantly lower in PCV group (P = 0.043–0.019, respectively); however, blood pressure at other times, hemoglobin levels, and mean heart rate were similar in two groups. Conclusions In patients undergoing posterior lumbar inter-body fusion surgery, mode of ventilation cannot make significant difference in terms of blood loss; however, some minor benefits in outcomes may lead to the selection of PCV rather than VCV. More studies with larger sample size, and investigating more factors may be needed.