Background: Type 2 diabetes individuals (T2D) show high levels of apolipoprotein CIII (ApoCIII), but its role in ectopic fat accumulation and impaired glucose metabolism is not clear. Aims: To investigate the effects of an isocaloric multifactorial diet, previously shown to reduce liver and pancreatic fat content, compared to a MUFA diet on plasma ApoCIII levels and its relationship with ectopic fat and β-cell function in patients with type 2 diabetes (T2D). Methods: In a randomized controlled parallel group study, thirty-six T2D individuals (20 M/16 F), 35-75 years, were assigned to an 8-week isocaloric multifactorial diet rich in MUFA, PUFA, fibre, polyphenols, and vitamins (n=20) or a MUFA rich diet (n=16). Before/after the intervention, glucose, insulin and plasma ApoCIII concentrations were measured at fasting and over a 3h test-meal with a similar composition as the assigned diet. β-cell function was assessed as the ratio between the total area under the curve (Total AUC) of the insulin to that of glucose. Liver and pancreatic fat were assessed by MRI. Results: Fasting plasma ApoCIII did not change significantly after both diets. Postprandial ApoCIII (Total AUC) tended to increase after the MUFA diet (2163±173 vs 2323±233, mg/dL·180min, baseline vs 8-week, mean±SEM, p=0.149) and to decrease after the Multifactorial diet (2252±247 vs 2117±228). Consequently, changes (8-week minus baseline) between diets were significantly different (Δ: +160±124 vs -134±15, p=0.043, respectively). In all the participants fasting ApoCIII changes correlated directly with changes in liver fat (r=0.357, p=0.032) and pancreatic fat (r=0.385, p=0.020), and inversely with β-cell function (r=-0.384, p=0.026). Postprandial ApoCIII correlated inversely with β-cell function (r=-0.402, p=0.018). Conclusions: In T2D individuals, a multifactorial diet reduces postprandial apo CIII; furthermore, changes in plasma ApoCIII levels were directly associated with changes in liver and pancreatic fat content and inversely with β-cell function.