Cesarean section (CS) rates are high. Epidemiological data supports increased risk of inflammatory conditions in the offspring born by CS. Epigenetic alterations occurring during the perinatal period may account for this risk. Cyclooxygenase-2 (COX2) has strong implications for inflammatory diseases. The methylation of COX2 of newborn infants was compared with respect to their mode of delivery. Ninety healthy term infants born by vaginal delivery (VD), planned cesarean section (PCS), or emergency CS (ECS) were recruited (30 infants in each group). For obstetric anesthesia, local (LA), regional (RA), or general (GA) anesthesia were used. Carefully selected exclusion criteria were implemented to eliminate any confounders with potential epigenetic effects. Umbilical artery blood samples were collected. Demographic and clinical characteristics, folate and CRP levels, and mean methylation levels of the COX2 gene promoter were determined. Except the birth weight and maternal age parameters, VD, PCS, and ECS were similar. The methylation percentage of COX2 was higher in ECS (16.9 ± 5.1) than VD (14.5 ± 4.1) and PCS (14.8 ± 2.9), albeit p was 0.064. Because of the dual anesthetic modality populations (RA and GA) in PCS and ECS and the recent literature on anesthetics and epigenetics, the anesthetic modality groups were also analyzed. The methylation percentage of COX2 was significantly different between LA, RA, and GA groups (14.5 ± 4.1, 13.9 ± 2.8, and 17.0 ± 4.6, respectively, p = 0.012). When the mode of delivery is the question of debate, the anesthetic modality should be remembered as an important epigenetic modulator. · Perinatal period is a vulnerable time period for epigenetic modulations.. · The mode of delivery is influential in any potential epigenetic alterations occurring perinatally.. · The obstetric anesthetic modality should be remembered as an important epigenetic modulator..