Pericardial adipose tissue (PAT) is positively associated with fatty liver and obesity-related insulin resistance. Because PAT is a well-known marker of visceral adiposity, we investigated the impact of weight loss on PAT and its relationship with liver fat and insulin sensitivity independently of body fat distribution. Thirty overweight nondiabetic women (BMI 28.2-46.8 kg/m(2), 22-41 years) followed a 14.2 ± 4-weeks low-calorie diet. PAT, abdominal subcutaneous (SAT), and visceral fat volumes (VAT) were measured by magnetic resonance imaging (MRI), total fat mass, trunk, and leg fat by dual-energy X-ray absorptiometry and intrahepatocellular lipids (IHCL) by ((1))H-magnetic resonance spectroscopy. Euglycemic hyperinsulinemic clamp (M) and homeostasis model assessment of insulin resistance (HOMA(IR)) were used to assess insulin sensitivity or insulin resistance. At baseline, PAT correlated with VAT (r = 0.82; P < 0.001), IHCL (r = 0.46), HOMA(IR) (r = 0.46), and M value (r = -0.40; all P < 0.05). During intervention, body weight decreased by -8.5%, accompanied by decreases of -12% PAT, -13% VAT, -44% IHCL, -10% HOMA2-%B, and +24% as well as +15% increases in HOMA2-%S and M, respectively. Decreases in PAT were only correlated with baseline PAT and the loss in VAT (r = -0.56; P < 0.01; r = 0.42; P < 0.05) but no associations with liver fat or indexes of insulin sensitivity were observed. Improvements in HOMA(IR) and HOMA2-%B were only related to the decrease in IHCL (r = 0.62, P < 0.01; r = 0.65, P = 0.002) and decreases in IHCL only correlated with the decrease in VAT (r = 0.61, P = 0.004). In conclusion, cross-sectionally PAT is correlated with VAT, liver fat, and insulin resistance. Longitudinally, the association between PAT and insulin resistance was lost suggesting no causal relationship between the two.