Use of current oral calcineurin inhibitors for the treatment of psoriasis is limited by toxicity.Evaluate the safety and efficacy of ISA247, a new oral calcineurin inhibitor, in plaque psoriasis patients.This 12-week, randomized, double-blind, placebo-controlled, parallel-group study included 201 plaque psoriasis patients with ≥ 10% body surface area involvement. Patients were randomized to placebo, ISA247 0.5 mg/kg/d, and ISA247 1.5 mg/kg/d groups. End points included a 2-point reduction in the Static Global Assessment score and a 75% reduction in the Psoriasis Area and Severity Index.A 2-point SGA reduction was achieved in 0% (placebo), 15.6% (0.5 mg/kg/d), and 45.1% (1.5 mg/kg/d) (P < .0001). A 75% reduction in the Psoriasis Area and Severity Index was achieved in 0% (placebo), 18.2% (0.5 mg/kg/d), and 66.7% (1.5 mg/kg/day) (P < .0001). While serum creatinine increased in patients treated with ISA247 1.5 mg/kg/d, it remained within the normal range.Longer-term studies are needed to evaluate the effect of ISA247 on renal function.ISA247 appears safe and effective for treating moderate to severe psoriasis.