This study examines the correlations between serum lipid levels and psychological distress. There were 4444 consecutive attendees of general health clinics who participated in the study. Psychological symptoms were measured by the Taiwanese version of the Symptoms Check List 90, revised (T-SCL-90-R). Levels of fasting serum lipids, including total cholesterol, total triglycerides and high-density lipoprotein cholesterol (HDL-C), were determined. Multiple linear regression analyses, with adjustment for confounders, revealed that the concentration of HDL-C had significant inverse associations with scores of depression, somatization and phobic anxiety. Women with an HDL-C level lower than 35 mg/dl scored significantly higher on depression, interpersonal sensitivity, phobia, anxiety, somatization and aggressive hostility, while subjects with a total cholesterol concentration lower than 160 mg/dl scored significantly higher on anxiety, aggressive hostility, phobia, and psychoticism. This study provides, for the first time, comprehensive data derived from the Taiwanese population on the link between lipids and psychological symptoms, revealing a reverse correlation between depression and serum concentrations of HDL-C.