Abstract Background Although an overall gender difference in prevalence of major depressive disorder (MDD) has been well established, several questions concerning gender differences in the clinical manifestation of depression remain. This study aims to identify gender differences in psychopathology, treatment, and public health consequences in patients with MDD. Methods Baseline data from the Netherlands Study of Depression and Anxiety (NESDA) were used, including 1115 participants (364 men, 751 women, mean age 41 years) with a DSM-IV diagnosis of current MDD. Characteristics studied included symptom profiles, comorbidity, treatment, and public health consequences. Results Women reported a younger age of onset of single (27.8 years vs. 31.6 years; p =0.001) and recurrent MDD (24.8 years vs. 27.6 years; p =0.014), a higher comorbidity of panic disorder with agoraphobia (24.9% vs. 17.3%; p =0.006) and life-time overall anxiety disorder (77.6% vs. 71.4%; p =0.029) than men. More men than women suffered from comorbid alcohol dependence or abuse (48.1% vs. 24.5%; p <0.001). An increased prevalence of atypical depression in women (24.6% vs. 17.3%; p =0.009) was found. Women were treated more frequently by an alternative caretaker (20.6% vs. 14.8%; p =0.025), men more often in mental health care organizations (61.0% vs. 53.7%; p =0.025). No gender differences in frequency of medication use or counseling were found. Limitations Cross sectional design. Conclusions Main gender differences in the clinical presentation of MDD concerned a younger age of onset, higher anxiety and lower alcohol use comorbidity and higher prevalence of atypical depression in women. These differences were accompanied by differences in health care use.