Introduction: While insulin resistance and obesity coexist, some obese individuals remain insulin-sensitive. We examined phenotypic and metabolic factors associated with insulin sensitivity in both muscle and liver in obese individuals. Methods: Sixty-four non-diabetic obese adults (29 males) underwent hyperinsulinaemic (15 and 80 mU/m2/min)-euglycaemic clamps with deuterated glucose. Top tertile subjects for glucose infusion rate during the high-dose insulin clamp (GIRHI) were assigned Musclesen and those in the lower two tertiles were assigned Muscleres. Secondarily, top tertile subjects for endogenous glucose production (EGP) suppression during the low-dose insulin clamp were deemed Liversen and the remainder Liverres. Clinical and laboratory parameters, muscle sympathetic nervous activity (MSNA) and visceral, subcutaneous, liver and pancreatic fat were compared. Results: Musclesen and Muscleres had similar body mass index and total fat (P ≥ 0.12), but Musclesen had lower HbA1c (P < 0.001) and systolic (P = 0.01) and diastolic (P = 0.03) blood pressure (BP). Despite similar subcutaneous fat (P = 0.83), Musclesen had lower visceral (P < 0.001) and liver (P < 0.001) fat. Liversen had lower visceral (P < 0.01) and liver (P < 0.01) fat and CRP (P=0.02) than Liverres. When subjects were grouped by both GIRHI and EGP suppression, insulin sensitivity at either muscle or liver conferred apparent protection from the adverse metabolic features that characterized subjects insulin-resistant at both sites. HDL-cholesterol, 1-hour glucose, systolic BP and triglycerides explained 54% of the variance in muscle insulin sensitivity. In men (but not women), MSNA burst frequency correlated inversely with liver insulin sensitivity (r = -0.53, P = 0.02) and positively with the C-reactive protein (CRP) and fibroblast growth factor (FGF)-19 (r = 0.57, P = 0.006 and r = -0.47, P = 0.03, respectively). Conclusions: Obese subjects who were insulin-sensitive at muscle and/or liver exhibited favourable metabolic features, including lower BP, liver and visceral adiposity. Basal sympathetic nerve activity related to liver insulin sensitivity in men, but not in women. MSNA associated with the circulating hepatokines CRP and FGF-19, suggesting a potential hepato-endocrine-autonomic axis. This study identifies factors associated with, and possibly contributing to, insulin sensitivity in obesity.