Purpose: To compare the efficacy of topical cyclosporine, punctal occlusion, and a combination for the treatment of dry eye. Methods: Patients with dry eye (N = 30) seen in a university-affiliated private practice were randomized to 1 of 3 treatments: cyclosporine 0.05% ophthalmic emulsion (RESTASIS) twice daily, lower-lid punctal plugs (PARASOL), or a plugs-cyclosporine combination. Tear volume, ocular surface staining, and artificial tear use were assessed at baseline and 1, 3, and 6 months. Results: All treatments improved Schirmer scores by 6 months (P ≤ 0.005 vs. baseline), with plug-containing regimens favored at 1 and 3 months (P < 0.001 vs. cyclosporine alone). Cyclosporine-containing regimens, but not plugs alone, improved rose bengal staining at 3 and 6 months (P ≤ 0.010 vs. baseline). Artificial tear use decreased with plug-containing regimens at 1 month and with all treatments at 3 and 6 months (P ≤ 0.005 vs. baseline). Combination therapy produced the greatest overall improvements and was superior to plugs alone in decreasing artificial tear use at 6 months (P = 0.012). Conclusions: All 3 regimens effectively treated dry eye. Plug-containing regimens increased wetness initially; cyclosporine appeared to promote long-term ocular surface health. The effects may be additive. Patients with punctal occlusion may benefit from adjunctive cyclosporine.