The aim of this paper is to assess the clinical effectiveness of orlistat used for the management of obesity. Nineteen electronic databases were searched for randomized controlled trials evaluating the effectiveness of orlistat for weight loss or maintenance of weight loss in overweight or obese patients. Each included trial was assessed for methodological quality. Statistical pooling was performed when trials were considered to be sufficiently similar. Twenty-three trials were eligible for inclusion. Placebo-controlled trials recruiting patients with uncomplicated obesity reported statistically significant differences in favour of orlistat for weight loss and changes in obesity-related risk factors at all time points. Trials in obese patients with defined risk factors at baseline showed similar results, however, smaller effect sizes were observed in patients with type 2 diabetes. The effectiveness of orlistat relative to other anti-obesity drugs is currently unclear. When orlistat was added to simvastatin, this proved to be more effective for weight loss than either drug used individually. Orlistat use is associated with a higher incidence of gastrointestinal adverse events compared with placebo. In conclusion, orlistat is more effective than placebo in promoting weight loss, maintenance of weight loss, and improving cardiovascular risk factor profiles. Baseline parameters of patients seen in clinical practice should be taken into account when considering treatment.