Background: First-line therapy for primary open-angle glaucoma and ocular hypertension generally involves prostaglandin analogue therapy. The relative efficacy of differing prostaglandin therapy is disputed. Methods: A meta-analysis was conducted of head-to-head randomized trials of prostaglandin therapies. We included randomized trials assessing head-to-head evaluations of prostaglandin analogues travoprost, latanoprost and bimatoprost in patients with predominantly primary open-angle glaucoma or ocular hypertension. Findings were interpreted in light of equivalence margins. Results: Our search identified 16 eligible trials, of which 15 were included in the meta-analysis. Trials were, in general, poorly reported. We pooled 9 trials assessing IOP-lowering effects of travoprost vs latanoprost (total n = 1098, weighted mean difference [WMD], -0.24 mmHg, 95% CI, -0.87 to 0.38, P = 0.45, I2 = 56%, 95% CI, 0 to 0.77, heterogeneity P = 0.01). Eight trials assessed travoprost vs bimatoprost (total n = 714, WMD, 0.88 mmHg, 95% CI, 0.13 to 1.63, P = 0.02, I2 = 56%, 95% CI, 0% to 78%, heterogeneity P = 0.02). And 8 trials assessed latanoprost vs bimatoprost (total n = 943, WMD, 0.73 mmHg, 95% CI, 0.10 to 1.37, P = 0.02, I2 = 47%, 95% CI, 0% to 74%, heterogeneity P = 0.06). Travoprost was associated with greater incidence of conjunctival hyperemia than latanoprost (RR 5.71, 95% CI, 1.81 to 18.02, P ≤ 0.001, I2 = 97%, 95% CI, 95 to 98, P ≤ 0.001). Five trials assessing latanoprost and bimatoprost revealed an elevated risk of conjunctival hyperemia with bimatoprost (RR 1.59, 95% CI, 1.02 to 2.48, P = 0.04, I2 = 76%, 95% CI, 16 to 88, P = 0.002). Conclusion: Randomized head-to-head evaluations of prostaglandin therapy demonstrate similar efficacy effects, but differing hyperemia effects. © 2009 Eyawo et al, publisher and licensee Dove Medical Press Ltd.