BACKGROUND: Recently there has been increased interest in the special mental health needs of women. We used data from the PRIME-MD 1000 study to assess gender differences in the frequency of mental disorders in primary care settings, and to explore the potential impact of these differences on health-related quality of life (HRQL). SUBJECTS AND METHODS: One thousand primary care patients (559 women) were interviewed during the PRIME-MD study, which was conducted at four primary care clinics affiliated with university hospitals throughout the eastern United States. Patients completed a one-page questionnaire in the waiting room prior to being seen by the physician; patients and physicians then completed together a clinician evaluation guide that used DSM-III-R algorithms to diagnose mood, anxiety, somatoform, eating, and alcohol related disorders. Health-related quality of life was assessed with the Medical Outcomes Study SF-20 General Health Survey. RESULTS: Women were more likely than men to have at least one mental disorder (43% versus 33%, P <0.05). Higher rates were particularly prominent for mood disorders (31% of women versus 19% of men, odds ratio [OR] = 1.9, 95% confidence interval [Cl] 1.4 to 2.6), anxiety disorders (22% versus 13%, OR = 1.9, Cl 1.3 to 2.8), and somatoform disorders (18% versus 9%, OR = 2.2, Cl = 1.5 to 3.4). Psychiatric comorbidity was also more common in women (26% of women had two or more mental disorders versus 15% of men, P <0.05). Unadjusted HRQL scores, ranging from 0 to 100, with 100 = best health, were all significantly lower in women than in men (eg, physical function = 67 in women versus 76 in men, P <0.0001; mental health = 69 in women versus 76 in men, P <0.0001). Many HRQL differences persisted after controlling for age, education, ethnicity, marital status, and number of physical disorders; however, differences in HRQL were eliminated in 5 of 6 domains after controlling for number of mental disorders. When compared with female patients of male physicians, female patients of female physicians demonstrated similar satisfaction with care, health care utilization, HRQL, and recognition rate of mental disorders. CONCLUSIONS: In the 1,000 patients of the PRIME-MD study, mood, anxiety, and somatoform disorders and psychiatric comorbidity were all significantly more common in women than men. The HRQL scores were poorer in women than men, although most of this difference was accounted for by the difference in prevalence of mental disorders. These data suggest that one of the most important aspects of a primary care physician's care of female patients is to screen for and treat common mental disorders.