To compare the efficacy of an intravitreal injection to a posterior subtenon injection of triamcinolone acetonide for the treatment of diffuse diabetic macular edema. Sixty patients with diabetes mellitus presenting with diffuse diabetic macular edema were recruited for the study. In each patient, one eye received a 4.0 mg (0.1 mL) intravitreal (IVT) injection of TA and the other eye was treated with a 40 mg (1.0 mL) posterior subtenon (PST) injection of triamcinolone acetonide (TA). We measured the visual acuity, the intraocular pressure (IOP) and the thickness of the macula using optical coherence tomography (OCT) before treatment and at one, three and six months after treatment. Eyes treated with PST showed 1-3 lines of improvement in Snellen's acuity from their pre-injection baseline visual status. The eyes in the IVT group showed 1-3 lines of improvement in Snellen's acuity in 80% of the treated eyes, but 20% of the treated eyes did not display any benefit at the end of six months. The difference in acuity between an IVT injection and a PST injection at six months post-treatment was statistically significant (p<0.05). The macular thickness of the eyes treated with an IVT injection was significantly reduced after one (222.7±13.4 μm; p<0.001) and three months (228.1±10.6 μm; p<0.001) of treatment. The eyes treated with a PST injection displayed a slow response and a significant improvement in macular thickness that was observed only after three months (231.3±10.9 μm; p<0.001). The difference between the eyes treated with an IVT injection (385.2±11.3 μm) and those treated with a PST injection (235.4±8.7 μm) was significantly different six months after treatment (p<0.001). The IOP of the eyes treated with an IVT injection was significantly increased after one (17.7±1.1 mm/Hg; p<0.020), three (18.2±1.2 mm/Hg; p<0.003) and six months (18.1±1.320 mm/Hg; p<0.007) when compared to the baseline value (16.1±1.4 mm/Hg). The eyes treated with a PST injection displayed no significant increase in IOP after one (16.4±1.2 mm/Hg; p<0.450), three (16.3±1.1 mm/Hg; p<0.630) and six months (16.2±1.1 mm/Hg; p<0.720) when compared to the baseline value (16.2±1.3 mm/Hg). A PST injection is equally effective and safer than an IVT injection of TA for the management of diffuse DME.