Anesthesia is able to modulate the balance between proinflammatory and anti-inflammatory cytokine production during surgery. The aim of this study is to assess the effect of three anesthesia approaches, total intravenous anesthesia (TIVA), inhalation anesthesia, and xenon anesthesia, on sieric levels of nitric oxide (NO), IL6, IL10, and TNF alpha in obese patients undergoing Roux-en-Y laparoscopic gastric bypass. Thirty adult morbidly obese patients (BMI > 35) scheduled for Roux-en-Y laparoscopic gastric bypass were randomly recruited and allocated to TIVA (N = 10), inhalation anesthesia (SEV, N = 10), and xenon anesthesia (XE, N = 10). Exclusion criteria were ASA IV, age < 18 or > 60 years, and Mallampati IV. Opioid dosage and ventilation parameters were standardized. Sieric levels of NO, IL6, IL10, and TNF alpha were assessed at T0 (before induction of anesthesia), T1 (end of surgery), and T2 (12 h after the end of surgery). We compared the relative cytokine level variations (delta) at T1 and T2 and the cytokine exposure levels calculated as the area under the curve (AUC) between T0 and T2 in the XE and non-XE (SEV + TIVA) groups. At T1, we found a significant Delta IL10 (reduction) and Delta TNF alpha (reduction) between XE and SEV (p < 0.05) and XE and TIVA (p < 0.05) groups. At T2, Delta IL10 was still significant. Furthermore, we found a reduced AUC value for TNF alpha in the XE group. Xenon anesthesia seems able to inhibit postoperative proinflammatory cytokine imbalance in morbidly obese patients undergoing Roux-en-Y laparoscopic gastric bypass; the reduced Delta TNF alpha at T1 and the reduced global exposition to TNF alpha in the XE group may explain the reduced Delta IL10 at T1 and T2.