OBJECTIVES: In a 6-week randomized, double-blind trial, olanzapine was associated with significant increases in triglycerides, low-density lipoprotein cholesterol (LDL), and total cholesterol (TC), while ziprasidone was not. We compared changes in risk of coronary heart disease (CHD) in olanzapine- and ziprasidone-treated patients in this trial. METHODS: We analyzed data from trial participants aged ?30 years using a Framingham data-based algorithm (Circulation 1998; 97:1837-1847) that calculates percentage risk of CHD over 10 years from age, gender, smoking status, presence of diabetes, high-density lipoprotein cholesterol (HDL), LDL or TC, and diastolic and systolic blood pressures. Changes from baseline to endpoint in percentage age-adjusted risk of CHD for men and women in ziprasidone and olanzapine treatment groups were compared using ANCOVA. RESULTS: Mean age was approximately 42 years for both the ziprasidone (range 30 to 55) and olanzapine (range 30 to 59) groups. In olanzapine-treated men (n = 55), risk of CHD increased by 0.8% from a baseline of 4.2% while in ziprasidone-treated men (n = 44) risk decreased by 0.2% from a baseline of 4.5% (p <0.05). Olanzapine-treated females (n = 18) had a 0.2% decrease in risk (baseline, 3%) while ziprasidone-treated females (n = 21) had a 0.4% increase (baseline, 2.5%) (p = NS). Analysis of treatment-associated changes in lipids in patients of all ages by gender found significant changes in TC, LDL, and triglycerides in olanzapine-treated men of all ages (n = 82) versus ziprasidone-treated men (n = 69) (p <0.005), with changes in triglycerides in olanzapine-treated women (n = 32) versus ziprasidone-treated women (n = 44) trending toward significance (p = 0.09). CONCLUSIONS: In a six-week trial, men treated with olanzapine experienced an increase in CHD risk that was significant versus a decrease in men treated with ziprasidone, while changes in risk did not differ significantly between olanzapine- and ziprasidone-treated women. These results paralleled changes in lipid profile. Investigation is warranted into effects of long-term treatment with atypical antipsychotics on risk of CHD.