The purpose of the present study was to examine whether the association between depression and the serum high-density lipoprotein cholesterol (HDL-C) is modified by symptom duration. Depressed patients (n = 88) and an age- and sex-matched group of healthy general population controls (n = 88) underwent a Structured Clinical Interview for DSM-IV (SCID), and depressed participants reported the duration of their symptoms. The serum levels of total cholesterol (TC), HDL-C, low-density lipoprotein cholesterol (LDL-C), triglycerides (TG) and non-HDL, and the ratios of LDL-C/HDL and TC/HDL-C were assessed. Major depressive disorder (MDD) subjects with a long symptom duration (>or=3 years) had lower levels of HDL-C compared with healthy controls or MDD subjects with a symptom duration <3 years. The likelihood for long symptom duration doubled for each 0.5-mmol/L decrease in HDL-C levels in regression models adjusted for age, gender, marital status, overweight, symptom severity, alcohol consumption, smoking, physical exercise, medication use, and non-HDL-C (P < 0.05). These findings suggest that a low serum HDL-C level, a risk factor for coronary heart disease, is specifically associated with long-term depressive symptomatology.