Background: Several studies have suggested an association between lipids or lipoproteins and depression, but findings are contradictory. However, previous studies did not always take into consideration potentially mediating factors or heterogeneity of symptoms, which may clarify contradicting findings. Method: We compared levels of serum total, lowdensity lipoprotein (LDL), and high-density lipoprotein (HDL) cholesterol and triglyceride between 761 subjects with current major depressive disorder (MDD) (Composite International Diagnostic Interview, based on the DSM-IV), 1,071 subjects with remitted MDD, and 629 controls, aged 18 to 65 years. Subjects participated in the baseline assessment of the Netherlands Study of Depression and Anxiety, which lasted from September 2004 to February 2007. We studied the impact of adjustment for sociodemographics, lifestyle-related covariates, and antidepressant use and examined the association between specific psychopathological characteristics and lipid/lipoprotein levels. Results: HDL cholesterol level was lower (P = .007) and triglyceride level was higher (P = .001) in current MDD versus remitted MDD and controls. After adjustment for level of education, body mass index (BMI), smoking status, and alcohol use, dissimilarities lost statistical significance. Depression severity, comorbid dysthymia, and melancholic and atypical features were all associated with lipids/lipoproteins, but most associations attenuated after adjustment for covariates, especially BMI. The association between melancholic features and lower HDL cholesterol (P = .038) and between atypical depression and higher total and LDL cholesterol (P = .004 and P = .002, respectively) persisted after full adjustment. Conclusions: Adverse lipoprotein patterns were found in patients with MDD. The fact that these associations diminished after adjustment for lifestyle-related factors, especially BMI, suggests that the unfavorable lipid/lipoprotein pattern among depressed subjects is mainly secondary to lifestyle-related factors. However, melancholic features were independently associated with lower HDL cholesterol, and atypical depression was independently associated with higher total and LDL cholesterol. © Copyright 2009 Physicians Postgraduate Press, Inc.