Our study wants to evaluate the effects of one year treatment with orlistat plus L-carnitine compared to orlistat alone on body weight, glycemic and lipid control, and insulin resistance state in type 2 diabetic patients. Two hundred and fifty-eight patients with uncontrolled type 2 diabetes mellitus (T2DM) [glycated hemoglobin (HbA_1c) > 8.0%] in therapy with different oral hypoglycemic agents or insulin were enrolled in this study and randomised to take orlistat 120 mg three times a day plus L-carnitine 2 g one time a day or orlistat 120 mg three times a day. We evaluated at baseline, and after 3, 6, 9, and 12 months these parameters: body weight, body mass index (BMI), HbA_1c, fasting plasma glucose (FPG), post-prandial plasma glucose (PPG), fasting plasma insulin (FPI), homeostasis model assessment insulin resistance index (HOMA-IR), total cholesterol (TC), low density lipoprotein-cholesterol (LDL-C), high density lipoprotein-cholesterol (HDL-C), triglycerides (Tg), retinol binding protein-4 (RBP-4), resistin, visfatin, high sensitivity-C reactive protein (Hs-CRP). We observed a faster, and better decrease of body weight, HbA_1c, FPG, PPG, LDL-C, HOMA-IR with orlistat plus L-carnitine compared to orlistat. A faster improvement of TC, Tg, FPI, resistin, RBP-4, visfatin, and Hs-CRP was reached with orlistat plus L-carnitine compared to orlistat. We can safely conclude that the association of orlistat plus L-carnitine was better than orlistat in improving body weight, glycemic and lipid profile, insulin resistance, and inflammatory parameters and no significant adverse events were recorded.