Oral ziprasidone shows increased bioavailability when taken with food. Here we describe 2 pharmacokinetic studies to quantify the impact of food on ziprasidone absorption. The first, an open-label, 6-way crossover study, investigated ziprasidone absorption in 8 healthy males. Subjects received oral ziprasidone (20, 40, and 80 mg) after an 8-hour fast or immediately following an FDA standard meal (60% fat). The second, an open-label, randomized, 3-way crossover study, explored the impact of dietary fat on ziprasidone absorption in 14 healthy subjects. Subjects received ziprasidone (40 mg) under 3 conditions: fasting, with an FDA standard meal (60% fat), and with a 30%-fat meal. In the first study, AUC was greater in fed than fasting states at each dose (20 mg, +48%; 40 mg, +87%; 80 mg, +101%). Increases in AUC and Cmax with dose were only linear in the fed state. In the second study, decreasing the fat content had a modest impact on ziprasidone absorption. AUC increased by 100% (60%-fat meal) and 80% (30%-fat meal) relative to the fasting state. These increases can be attributed to enhanced ziprasidone solubilization, leading to greater intestinal absorption. Less pharmacokinetic variability was observed in the fed state, suggesting more consistent absorption of ziprasidone when taken with food. These results demonstrate that administration of ziprasidone with food is crucial to ensure optimal absorption and necessary for linear pharmacokinetics. Food will also provide greater consistency in daily systemic exposure to ziprasidone and, thus, better symptom control and tolerability.