Intraocular pressure (IOP) reduction is currently the only therapeutic approach demonstrated to preserve visual function in patients with glaucoma. The first line of glaucoma treatment consists of topical IOP-lowering medications, usually initiated as monotherapy. A significant proportion of patients require more than one medication to reach a target IOP at which optic nerve damage will not progress. As prostaglandin analogues (PGAs) are the most effective class for reducing IOP, one of the other commonly used classes (β-adrenoceptor antagonist [β-blocker], carbonic anhydrase inhibitor or α(2)-adrenoceptor agonist) is frequently combined with a PGA. In the last decade, the use of fixed combinations containing two medications in a single bottle has steadily increased. Fixed combinations have the potential to simplify the dosing regimen, increase patient adherence, avoid the washout effect of the second drop on the first medication instilled, decrease exposure to preservatives and, sometimes, reduce the cost of treatment. Clinical trials have evaluated PGA-based fixed combinations versus unfixed combinations (individual components administered concomitantly) or versus individual monotherapies; however, any advantage that the fixed combinations may have in terms of IOP-lowering efficacy is still debated. For these reasons, the PGA-based fixed combinations are not approved by regulatory authorities in some countries, such as the US. We review the published studies evaluating the efficacy and tolerability of the IOP-lowering unfixed and fixed combination therapies with PGAs. Regarding unfixed combinations, the review shows that α(2)-adrenergic agonists-PGA and carbonic anhydrase inhibitor-PGA combinations seem to be at least as effective at reducing IOP as the β-blocker-PGA combinations. As for the fixed combinations, the review shows that the three PGA-timolol fixed combinations are more effective than their component medications used separately as monotherapy and are better tolerated than the three respective prostaglandins. The three PGA-timolol fixed combinations are less effective at reducing IOP than the unfixed combinations but are better tolerated. The advantage of the fixed combinations in terms of patient adherence and persistence is supported by a very small number of studies and remains to be more accurately determined. Most studies, but not all, seem to show that PGA-timolol fixed combinations are more effective than other available β-blocker fixed combinations (dorzolamide-timolol fixed combinations) at reducing IOP and are similarly tolerated.