The purpose of this study was to test whether the melanocortin-4 receptor (MC4R) is critical in the development of hypertension associated with obesity and its metabolic disorders. MC4R-deficient homozygous (−/−) and heterozygous (+/−) and wild-type (WT) C57BL/6J mice 17 to 19 weeks old (n=5 to 7 per group) were implanted with telemetry devices for monitoring 24-hour mean arterial pressure (MAP) and heart rate (HR). After 3-day stable control measurements on normal-salt diet (NSD; 0.4% NaCl), mice received a high-salt diet (HSD; 4% NaCl) for 7 days, followed by 3-day recovery on NSD. MC4R (−/−) mice were severely obese compared with MC4R (+/−) and WT mice (body weight 48±1.5 versus 31±0.6 and 30±0.5 g respectively). On NSD, MAP was similar in all groups of mice (MC4R (−/−) 110±3 mm Hg; MC4R (+/−) 109±2 mm Hg; WT 114±2 mm Hg), and HR in MC4R (−/−) was lower than in WT (604±5 versus 645±9 bpm; P<0.05) but not different from MC4R (+/−) (625±13 bpm) mice. HSD did not significantly alter MAP or HR in any of the groups. Epididymal and retroperitoneal fat weights and plasma leptin levels were several-fold greater in MC4R (−/−) compared with MC4R (+/−) and WT mice. Plasma insulin and glucose levels were also significantly greater in MC4R (−/−) than in MC4R (+/−) and WT mice. These data suggest that despite obesity, visceral adiposity, hyperleptinemia, and hyperinsulinemia, MC4R (−/−) mice are neither hypertensive nor salt sensitive, indicating that a functional MC4R may be necessary for the development of hypertension associated with obesity and its metabolic abnormalities.