Short-term markers of successful visceral adipose tissue (VAT) loss are needed. Urinary F-isoprostanes might serve as a marker for intensified lipid metabolism, whereas circulating IL-6 might stimulate fat oxidation and enhance mobilization of VAT. Objectives: This pilot study was designed to explore the hypotheses that 1) reduction in VAT is associated with increase in IL-6, and 2) that increases in urinary F-isoprostanes are associated with increases in IL-6 and reduction in VAT. Methods: Eighteen participants (aged 60-75 y, BMI 30-40 kg/m2) were randomly assigned to either a very-low-carbohydrate diet (VLCD; <10:25:>65% energy from carbohydrate:protein:fat) or a low-fat diet (LFD; 55:25:20%) for 8 wk. Changes in fat distribution were assessed by MRI. Four urinary F-isoprostane isomers were quantified in 24-h urine collection using LC-MS/MS analyses. Changes in 4 F-isoprostane isomers were summarized using factor analysis (Δ-F-isoprostane factor). Statistical significance was set at P < 0.1. Results: Within the VLCD group, change in VAT was inversely associated with change in IL-6 (r = -0.778, P = 0.069) and Δ-F-isoprostane factor (r = -0.690, P = 0.086), demonstrating that participants who maintained higher concentrations of F-isoprostane factor across the intervention showed greater decreases in VAT. A positive relation between Δ-F-isoprostane factor and change in IL-6 was observed (r = 0.642, P = 0.062). In the LFD group, no significant associations between changes in VAT, F-isoprostane factor, or IL-6 were observed. Conclusions: Results from this exploratory study in older adults with obesity suggest that, in the context of a VLCD, IL-6 could be involved in VAT mobilization, and urinary F-isoprostanes could reflect intensified oxidation of mobilized fatty acids. Trial registration: This study is registered at clinicaltrials.gov as NCT02760641.