Background: Hypertension is the most common chronic condition globally, contributing to an increased risk of cardiovascular disease and premature death. Despite advances in treatment options, approximately 10% of patients have resistant hypertension, characterized by elevated blood pressure that does not respond to treatment. The gut microbiome is now increasingly recognized to play a role in the development and pathogenesis of several diseases, including hypertension, although the exact mechanisms remain unclear. Method: The aim of the present study was to investigate circulating levels of short-chain fatty acids, metabolites produced by gut bacteria, in essential (n = 168) and resistant hypertensive (n = 27) patients, compared with healthy controls (n = 38). Results: Serum acetate was significantly lower in the resistant hypertensive population, compared with both the normotensive controls and those with essential hypertension (748 ± 89 versus 1335 ± 61 and 1171 ± 22 nmol/ml, P < 0.0001). Acetate was also significantly lower in treated versus untreated hypertensive patients or controls (1112 ± 27 versus 1228 ± 40 and 1327 ± 63 nmol/l, P < 0.01), with this finding more pronounced with increasing number of antihypertensive therapies. In contrast, propionate was lower and butyrate significantly higher in those with essential hypertension compared with controls (propionate: 25.2 ± 7.5 versus 58.6 ± 7.6 nmol/ml, P < 0.0001; butyrate: 46.5 ± 3.5 versus 14.7 ± 9.9 nmol/ml, P < 0.01). A novel and perhaps clinically relevant observation was the significant difference in acetate and propionate levels between patients taking ACE inhibitors or angiotensin-receptor blockers. Conclusion: The present study has highlighted differences in circulating short-chain fatty acids in different hypertensive phenotypes and a possible influence of drug number and class. Although further research is necessary, this may represent a novel therapeutic target, particularly in patients with resistant hypertension.