Previous studies on the association between affective disorders and the metabolic syndrome yielded inconclusive results. Therefore, we examined the prevalence of the metabolic syndrome in 230 men and women with unipolar major depressive disorder during inpatient treatment and compared it to 1,673 subjects from primary care from a similar region in northern Germany. We used the AHA/NHBLI criteria to determine the rate of metabolic syndrome (MetS) and each single criterion of MetS in both groups. The age-standardized prevalence of MetS was 2.4× as high in patients with major depressive disorder (MDD) compared with data from comparison subjects (41.0% vs. 17.0%). With respect to the single criteria, elevations were found in MDD patients for fasting glucose and triglycerides in both genders, and waist circumference in women. Men in the patient and the comparison groups were found to have higher rates of increased fasting glucose and triglycerides than women in the respective groups. Factors associated with the MetS in MDD patients comprise body mass index and the severity of depression. Our results demonstrate an increased prevalence of the MetS in men and women with MDD. Interventions for the frequently untreated metabolic abnormalities and careful screening for physical health conditions among people with MDD are warranted.