<p>Volatile anesthetics modulate inflammatory responses, but it remains unclear whether desflurane and sevoflurane differ in their effects on postoperative inflammation. We evaluated in this secondary analysis of a prospective randomized trial, the effect of desflurane versus sevoflurane anesthesia on postoperative inflammatory biomarkers in older adults undergoing minor- to moderate-risk noncardiac surgery. We included all 190 patients who were enrolled in the main trial in this analysis. We administered desflurane or sevoflurane, aiming for a BIS value of 50 ± 5. C-reactive protein, Interleukin-6, and Procalcitonin concentrations were measured preoperatively, within one hour after surgery, and on the second postoperative day. We observed no significant difference in maximum postoperative Interleukin-6 (8.11 pg ml^− 1 [IQR 4.77; 15.7] versus 7.84 pg ml^− 1 [IQR 4.67; 12.62]) (<i>p =</i> 0.357), C-Reactive Protein (0.32 mg dl^− 1 [IQR 0.13; 0.9] versus 0.26 mg dl^− 1 [IQR 0.13; 0.83] (<i>p =</i> 0.433), and Procalcitonin (0.04 ng ml^− 1 [IQR 0.03; 0.07] versus 0.04 ng ml^− 1 [IQR 0.03; 0.06]) (<i>p =</i> 0.709) between desflurane and sevoflurane anesthesia. We did not find a significant difference in the concentration of postoperative inflammatory biomarkers. While prior studies indicated different effects on inflammation between different types of volatile anesthetics, we cannot observe this in our study. Our findings indicate that in this specific clinical setting, the choice between sevoflurane or desflurane for minor- to moderate-risk noncardiac surgery does not significantly affect the minor postoperative inflammatory response in older patients when volatile anesthetics at low MAC concentrations are administered.</p>