The goal of our study was to evaluate the burden of endometriosis in the community by comparing healthcare resource utilization, total direct medical costs, infertility, and comorbidity rates of women with and without a diagnosis of endometriosis. A retrospective case-control study was performed using the databases of a 2.1 million-member nationwide healthcare plan. The study population included women aged 15-55 years enrolled in the healthcare plan. Women with a diagnosis (ICD-9) of endometriosis were compared to controls without diagnosed endometriosis. Women were individually matched (1:4) on age and residence area. Patient characteristics were described, including infertility, comorbidities, and annual healthcare resource utilization. Total direct medical costs were analyzed in a generalized linear model adjusting for age. Women with endometriosis ( = 6146, mean age ± SD: 40.4 ± 8.0 y) were significantly more likely than controls ( = 24,572) to have a lower BMI and a higher socioeconomic status. After adjusting for BMI and socioeconomic status, endometriosis was significantly associated with infertility (OR = 3.3; 95% CI 3.1-3.5), chronic comorbidities, higher utilization of healthcare services (hospitalization: OR = 2.3; 95% CI 2.1-2.5), pain medications, and antidepressants. Women aged 15-19 y with endometriosis had substantially higher utilization of primary care visits (57.7% vs. 14.4%) and oral contraceptive use (76.9% vs. 9.6%). Direct medical costs associated with endometriosis were higher than those for controls (OR = 1.75; 95% CI 1.69-1.85). Endometriosis is associated with a high burden of comorbidities, increased healthcare resource utilization, and excess costs, particularly for younger patients whose healthcare needs may differ widely from the older population.