Previous studies have suggested that patients with major depressive disorder may have lower cholesterol levels compared to healthy controls. The purpose of this study was to examine the relationship between pretreatment serum cholesterol levels and clinical response to treatment with fluoxetine among outpatients with major depression. Three hundred and twenty-two depressed outpatients meeting DSM-III-R criteria for major depressive disorder were enrolled in an 8-week, fixed-dose, open trial of fluoxetine 20 mg/day. Nonfasting serum cholesterol levels were obtained for all patients before starting fluoxetine. All patients were drug free for a minimum of 2 weeks prior to the onset of the study. Clinical response was defined as a 50% or greater decrease in the 17-item Hamilton Rating Scale for Depression (HAM-D-17) score at endpoint compared to baseline. Cholesterol levels were classified as either elevated (defined as a level equal to or greater than 200 mg/dL) or nonelevated (defined as a level less than 200 mg/dL). Among the 322 outpatients, 51.6% were classified as having elevated and 48.4% as having nonelevated cholesterol levels at baseline (mean cholesterol level 238.6 +/- 33.4 mg/dL vs. 170.4 +/- 22.2 mg/dL, respectively). Depressed patients with elevated cholesterol levels did not significantly differ in gender ratio but were significantly older than depressed patients with nonelevated cholesterol levels (P <.0001). After adjusting for age, gender, and Body Mass Index (BMI), depressed patients with elevated cholesterol levels were significantly more likely to be nonresponders to fluoxetine treatment than were depressed patients with nonelevated cholesterol levels (P < 0.05). Elevated serum cholesterol levels appear to be associated with poorer response to fluoxetine treatment. Further studies are needed to confirm our findings.