The effectiveness and safety of diflorasone diacetate 0.05% in an optimized cream vehicle (Psorcon Cream) and fluocinonide 0.05% cream (Lidex Cream) in the management of moderate-to-severe psoriasis was compared in a double-blind multicenter 2-week study enrolling 100 patients. A randomized bilateral-paired comparison study design was used. The efficacy results showed that the mean total scores (erythema, scaling, and induration) were significantly lower for diflorasone diacetate-treated sites than for the comparable fluocinonide-treated sites at days 7 and 14 (P<0.001). The comparative evaluations made by the investigators were also more favorable for diflorasone diacetate-treated sites than for fluocinonide-treated sites at day 14 (P<0.001), and the global evaluations of effectiveness done by the investigators favored the diflorasone diacetate-treated sites (P<0.001). More patients rated the improvement in their diflorasone diacetate-treated sites superior to that in their fluocinonide-treated sites (59% vs 20%) at day 14 (P<0.001). Patients also found diflorasone diacetate treatment to be more cosmetically acceptable than fluocinonide treatment (70% vs 44% rated treatment as good to excellent). No adverse experiences were reported following diflorasone diacetate treatment. These findings demonstrate that this cream formulation of diflorasone diacetate is an effective, well-tolerated, and cosmetically acceptable treatment for the management of moderate-to-severe psoriasis.