Background: Increased concentrations of low density lipoprotein cholesterol (LDL-C), as well as of small dense LDL-C (sdLDL-C), are considered as cardiovascular risk factors. Objective: An assessment of the effects of ezetimibe and orlistat administration, alone or in combination, on LDL-C and sdLDL-C levels (primary endpoint), as well as on anthropometric variables and metabolic parameters (secondary endpoints) in overweight and obese patients [body mass index (BMI) > 28 kg/m(2)] with hypercholesterolaemia [total cholesterol > 200 mg/dL (5.2 mmol/L]. Methods: Eighty six subjects were prescribed a low-fat low-calorie diet and were randomly allocated to receive orlistat 120 mg, 3 times daily (0 group), ezetimibe 10 mg/day (E group) or both (OE group) for 6 months. Results: Significant reductions in LDL-C (-19%, -21 %, -32% in groups O, E and OE, respectively, all p<0.01 vs. baseline) and sdLDL-C levels (-45%, -48%, -76% in groups O, E, OE, respectively, all p<0.01 vs. baseline) were observed. Group OE experienced a significantly greater reduction in LDL-C and sdLDL-C levels compared with groups 0 and E (p< 0.05). Furthermore, significant reductions of BMI, homeostasis model assessment (HOMA) index, serum uric acid, transaminase activities and plasma lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) activity were observed in the O and OE groups. Gamma-glutamyl transpeptidase activity and Lp-PLA(2) activity in overweight and obese hypercholesterolaemic improved significantly more with the combination treatment patients than either drug alone. Furthermore, orlistat, compared with either orlistat or ezetimibe monotherapy. alone or in combination with ezetimibe, Conclusions: Orlistat and ezetimibe combination additionally improved several anthropometric and metabolic had a more favourable effect on LDL-C and sdLDL-C levels variables.