There is still no study investigating the prognostic performance of CD14⁺⁺CD16⁻, CD14⁺⁺CD16⁺ and CD14⁺CD16⁺⁺ monocyte subpopulations in complicated intra-abdominal infections (cIAIs); therefore, we aimed to evaluate the association between monocyte subtypes and outcome in such patients. A single-center prospective study was conducted at a University Hospital Stara Zagora between November 2018 and August 2021. Preoperatively and on the 3rd postoperative day (POD), we measured the levels of CD14⁺⁺CD16⁻, CD14⁺⁺CD16⁺ and CD14⁺CD16⁺⁺ monocytes in peripheral blood using flow cytometry in 62 patients with cIAIs and 31 healthy controls. Nine of the 62 patients died during hospitalization. Survivors had higher pre-surgery percentages of CD14⁺⁺CD16⁻ classical monocytes and higher percentage of these cells predicted favorable outcome in ROC analysis (AUROC = 0.781, p = 0.008). The CD14⁺⁺CD16⁺ intermediate monocyte percentages were higher in non-survivors both pre- and postoperatively but only the higher preoperative values predicted a lethal outcome (AUROC = 0.722, p = 0.035). For CD14⁺CD16⁺⁺ non-classical monocytes, non-survivors had lower percentages on day 3 post-surgery and low percentage was predictive of lethal outcome (AUROC = 0.752, p = 0.046). Perioperative levels of monocyte subpopulations in peripheral blood show a great potential for prognostication of outcome in patients with cIAIs.