Different diets have distinct impacts on glucose homoeostasis, for which insulin sensitivity (IS) after a meal (postprandial IS) is highly relevant. Postprandial IS depends upon hepatic parasympathetic activation and glutathione content elevation. We tested the hypothesis that postprandial IS is compromised in high-fat diet (HFD)-induced obesity. Sprague–Dawley rats were fed a standard diet (STD, n 10), 1-week HFD (n 9) or 4-week HFD (n 8). IS was tested in postprandial state using the rapid IS test (RIST) before and after the blockade of the parasympathetic nerves (atropine, 1 mg/kg); parasympathetic-dependent IS was obtained from the difference between control and post-atropine RIST. Fasting IS was also assessed in the STD-fed rats (n 4) and 4-week HFD-fed rats (n 3) using the RIST. Whole-body fat and regional fat pads were heavier in the 1-week HFD-fed rats (79·8 (se 7·9) and 23·7 (se 1·0) g, respectively) or 4-week HFD-fed rats (106·5 (se 6·1) and 30·1 (se 1·4) g, respectively) than in the STD-fed rats (32·5 (se 3·7) and 13·7 (se 1·0) g, respectively; P < 0·001). Fasted-state IS was similar between the groups studied. Postprandial IS was higher in the STD-fed rats (185·8 (se 5·6) mg glucose/kg body weight (bw)) than in both the 1-week HFD-fed rats (108·8 (se 2·9) mg glucose/kg bw; P < 0·001) and 4-week HFD-fed rats (69·3 (se 2·6) mg glucose/kg bw; P < 0·001). Parasympathetic-dependent IS was impaired in both HFD-fed groups (STD, 108·9 (se 3·9) mg glucose/kg bw; 1-week HFD, 38·6 (se 4·2) mg glucose/kg bw; 4-week HFD, 5·4 (se 1·7) mg glucose/kg bw; P < 0·001). Total (postprandial) and parasympathetic-dependent IS correlated negatively with whole-body fat (R2 0·81 and 0·87) and regional adiposity (R2 0·85 and 0·79). In conclusion, fat accumulation induced by HFD is associated with postprandial insulin resistance, but not with fasting insulin resistance. HFD-associated postprandial insulin resistance is largely mediated by impairment of parasympathetic-dependent insulin action, which correlates with adiposity.