ObjectiveThe purpose of our study was to investigate the effect of gender on postoperative pain, sleep quality, and recovery outcomes in patients undergoing VATS surgery under general anesthesia. MethodPerioperative peripheral blood inflammatory markers system inflammation Index (SII) was recorded for perioperative inflammatory response. The visual analog scale (VAS) was used to evaluate pain level. And the Athens Insomnia Scale (AIS) was evaluated on the night before surgery (sleep preop 1), the first night after surgery (sleep POD 1), and the third night after surgery (sleep POD 3) for postoperative sleep. ResultIn this prospective cohort study, 79 males and 79 females were consecutively included. Females had significantly higher pain score (both rest and cough pain) compared to the males at 3 h after the surgery (3.85 ± 1.2 vs. 3.16 ± 1.1) (rest) (p < 0.001) and 5.10 ± 1.3 vs. 4.46 ± 1.6 (coughing) (p = 0.006)). Patients in the male group had significantly lower AIS scores than those in the female group at Sleep POD 1 and Sleep POD 3 (p = 0.024 and p = 0.045). And in both groups, postoperative SII was increased and statistically significant compared to preoperative SII (p < 0.001, respectively). Women presented higher levels of SII on the first day after surgery, and the increase of postoperative SII in females groups was significantly higher than that in male group when compared to preoperative SII (1806.33 ± 1314.8 vs 1430.55 ± 958.4) (p = 0.042). ConclusionThese findings highlight the complex multidimensional nature of postoperative pain, nausea and vomiting, sleep quality and the potential contributory role of sex in shaping these outcomes. Women had worse sleep quality, higher postoperative inflammatory response level and pain level than men.