BACKGROUND AND PURPOSE: The human sweet taste receptor, TAS1R2-TAS1R3, conveys sweet taste in the mouth and may help regulate glucose metabolism throughout the body. Ibuprofen and naproxen are structurally similar to known inhibitors of TAS1R2-TAS1R3 and have been associated with metabolic benefits. Here, we determined if ibuprofen and naproxen inhibited TAS1R2-TAS1R3 responses to sugars in vitro and their elicited sweet taste in vivo, in humans under normal physiological conditions, with implications for effects on glucose metabolism. EXPERIMENTAL APPROACH: Human psychophysical taste testing and in vitro cellular calcium assays in HEK293 cells were performed to determine the effects of ibuprofen and naproxen on sugar taste signalling. KEY RESULTS: Ibuprofen and naproxen inhibited the sweet taste of sugars and non-nutritive sweeteners in humans, dose-dependently. Ibuprofen reduced cellular signalling of sucrose and sucralose in vitro with heterologously expressed human TAS1R2 (hTAS1R2)-TAS1R3 in human kidney cells. To mirror internal physiology, low concentrations of ibuprofen, which represent human plasma levels after a typical dose, inhibit the sweet taste and oral detection of glucose at concentrations nearing post-prandial plasma glucose levels. CONCLUSION AND IMPLICATIONS: Ibuprofen and naproxen inhibit activation of TAS1R2-TAS1R3 by sugar in humans. Long-term ibuprofen intake is associated with preserved metabolic function and reduced risk of metabolic diseases such as Alzheimer's, diabetes and colon cancer. In addition to its anti-inflammatory properties, we present here a novel pathway that could help explain the associations between metabolic function and chronic ibuprofen use.