Impairment in cognitive flexibility and set shifting abilities has been described in obesity. This alteration is critical as it can interfere with obesity management strategies. Recent evidences suggest that chronic low-grade inflammation may be involved in cognitive deficits associated with obesity, but the potential involvement in reduced flexibility remains unknown. The objective of this study was to assess the contribution of low-grade inflammation, determined by circulating levels of high-sensitivity C-reactive protein (hsCRP), in reduced cognitive flexibility and shifting abilities of obese subjects relatively to a group of non-obese participants. Performance in the intra/extra-dimensional set shift (IED) test, extracted from the CANTAB, was assessed in 66 obese subjects and 20 non-obese participants. Obese subjects with concentrations of hsCRP above 5 mg/L exhibited reduced performance on the IED test in comparison to obese subjects with lower levels of hsCRP and non-obese participants. This difference was particularly manifest in the number of errors made during the extra-dimensional shift (EDS errors). In contrast, performance before the extra-dimensional shift was spared. Linear regression analyses revealed that the association between obesity and IED alterations was significant only when the condition hsCRP >5 mg/L was entered in the model. These findings are important as they indicate that, rather than obesity itself, low-grade inflammation represents a major contributor of IED performance in obese subjects.