Short chain fatty acids (SCFAs), including propionate, are the main metabolic by-products in the fermentation of non-digestible dietary fibre by the gut microbiota. SCFAs have wide-ranging effects in vivo, and their receptors, free fatty acid receptor 2 (FFAR2) and free fatty acid receptor 3 (FFAR3), are expressed at numerous tissue sites. Sodium propionate supplementation has been shown to increase energy expenditure, induce sympathetic neuron action potentials and protect against diet-induced obesity in murine trials. The raised energy expenditure has been accompanied by increased rates of whole-body lipid oxidation. Observations in humans are currently lacking, therefore, the objective of the present study was to investigate the effects of oral sodium propionate supplementation on resting energy expenditure (REE) and lipid oxidation in healthy human volunteers. 18 volunteers (Age: 25±1 y; Body Mass Index 24.1±1.2 kg/m2) were recruited for this randomised, double blind, placebo-controlled, crossover trial. Volunteers received either 6.8 g sodium propionate (Propionate) or 4.2 g sodium chloride (Placebo) capsules following an overnight fast during two standardised 180 min study visits. Indirect calorimetry was used to measure REE, respiratory exchange ratio (RER) and substrate oxidation rates. Levels of circulating propionate were higher in the Propionate trial at 180 min compared with Control (3.04±0.26 vs 5.25±0.65 μmol/l; P=0.005). Propionate increased mean REE (1.25 vs 1.30 kcal/min; P=0.036). This effect was seen in conjunction with a reduction in mean RER (0.88±0.02 vs 0.85±0.02; P=0.040) and corresponding increase in mean whole-body lipid oxidation rates (0.037±0.009 vs 0.049±0.009; P=0.048) over 180 min. The present study observed that oral sodium propionate supplementation increases REE via an increase in lipid oxidation in humans, corroborating findings in animal trials. In humans, >90% of propionate absorbed from the gut lumen undergoes hepatic metabolism, thus it is plausible that these observed effects were primarily due to an increase in hepatic lipid oxidation. Future work may utilise hepatic MR spectroscopy, to investigate the long-term effects of propionate administration on hepatic metabolic processes.