This study aimed to compare the nasal decolonization efficacy and comfort between chlorhexidine gluconate (CHG) and povidone-iodine (PVP) to provide an evidence basis for clinical guidance. A prospective, randomized, single-blinded, noninferior clinical trial was conducted in 174 patients with pituitary neuroendocrine tumors (PitNETs) who were scheduled to undergo transsphenoidal surgery. The noninferiority margin was δ=-0.1. The primary outcome was the effective rate of disinfection. The secondary outcomes included post-operative inflammatory indicators, the intracranial infection rate, and the proportion of intracranial infection. The effective clearance rate of post-operative nasal bacteria was nonsignificantly different between the CHG and PVP groups (88.64% vs. 82.56%; between-group difference 6.10%; 95% CI [-5.30 to 17.50]). There was no significant difference in the incidence of post-operative central nervous system infections or serum inflammation-related indications between the two groups, but sterilization tended to occur quicker and last longer in the CHG group. CHG seemed to have advantages in terms of comfort, including less nasal irritation, less pungency, and better intranasal coloration. CHG and PVP have equal efficacy in nasal decolonization before transsphenoidal surgery, but CHG seems to have comfort-related advantages in terms of less nasal irritation, less pungency, and better intranasal coloration.