Food increases the bioavailability of ziprasidone. This study explored the effect of calorie intake and fat content of food on ziprasidone bioavailability in a randomized, 6-way crossover study in 15 patients taking oral ziprasidone 80 mg bid as their standard antipsychotic therapy. There were 6 randomized meal conditions (fasted, low-calorie/low-fat, low-calorie/high-fat, medium-calorie/high-fat, high-calorie/low-fat, and high-calorie/high-fat); each crossover period was separated by at least 3 days for washout of the previous meal condition. Serial blood samples were obtained over the 12 hours post-dose. Pharmacokinetic parameters were calculated by noncompartmental methods. Maximum exposures were observed with medium-calorie and high-calorie meals and were about twice that observed under fasting conditions. The medium-calorie meal (ie, 500 calories) was associated with exposures within approximately 5% (within the equivalence limits of 90% CI) of the high-calorie meals (1000 calories). Low-calorie meals (250 calories) were associated with exposures that were substantially lower (approximately 60% to 90% lower) than those of medium-calorie and high-calorie meals, and approached exposures seen under fasting conditions. The ziprasidone exposures under medium-calorie and high-calorie meals had less variability than those of under low calorie and fasting conditions. In conclusion, ziprasidone exposure did not vary with the fat content (high or low) of a meal and a medium-calorie meal produced near maximal exposures.