We assessed efficacy and safety of a new anti-ischemic agent, ranolazine, during a randomized, double-blind, placebo-controlled crossover study. In the qualifying phase, we withdrew at least 1 antianginal drug from the drug regimen of 312 patients with chronic stable angina while they took placebo. After exercise time had shortened by > or =1.0 minute, we randomly assigned patients to receive either immediate-release ranolazine in 3 dosing regimens or placebo during each treatment period. After each week of treatment, we measured exercise tolerance and ranolazine plasma concentrations at both peak and trough. All exercise parameters significantly (p< or =0.02) improved (intention-to-treat analysis) with ranolazine (all regimens combined) at mean peak plasma concentrations ranging from 1,576 to 2,492 ng/ml compared with placebo without differences in double product. Although similar trends persisted at mean trough, plasma concentrations (range 275 to 602 ng/ml), only the time to 1.0 mm ST-segment depression remained statistically significant. In conclusion, immediate-release ranolazine is effective and well tolerated. However, this immediate-release short-acting formulation with this dosing regimen is not adequate for continuous protection. Either larger or more frequent doses or a sustained-release formulation would be required for clinical use.