OBJECTIVES:  To characterize health care spending associated with endometriosis-related comorbidities. METHODS:  Women aged 18-49 with endometriosis (N=128,088) were extracted from 2006-2015 de-identified Clinformatics^TM  DataMart (Optum Insight, Eden Prairie, MN) claims data. Endometriosis was identified by ICD-9 diagnosis code 617.x on ≥1 inpatient or emergency room claim or ≥2 outpatient claims. For 22 comorbidities, comorbidity patients (first diagnosis after initial endometriosis diagnosis) and controls (no comorbidity diagnosis) were identified. Controls were matched 1:1 to comorbidity patients using geographic region, insurance plan type, age and baseline healthcare spending. Index date was defined as first comorbidity diagnosis date for comorbidity patients, and equal number of days after earliest endometriosis claim for controls. Total medical and pharmacy spending was measured during 12 months before and after the index date. Pre-post differences for comorbidity patients and controls were compared using difference-in-differences linear regression. RESULTS:  The number of patients with each of the 22 comorbidities varied between 121 and 16,177. Mean age was 37 years. Spending was significantly higher after onset of 8 comorbidities: breast cancer (+$54,453), ovarian cancer (+$19,881), pregnancy complications (+$7,728), systemic lupus erythematosus/rheumatoid arthritis/Sjogren’s/multiple sclerosis (+$5,073), infertility (+$4,630), uterine fibroids (+$4,007), ovarian cyst (+$3,866) and headache (+$373) (p<0.001 except for headache [p=0.045].) Spending was significantly lower for fatigue (−$385), cystitis/UTI (−$1,312) and eczema (−$1,626) (p<0.001 except for fatigue [p=0.048]). Spending was not different for endometrial cancer, interstitial cystitis, stress, pelvic inflammatory disorder, mood disorders, constipation, fibromyalgia, depression, sprue, hypothyroidism, and irritable bowel syndrome. Difference-in-differences estimates were significantly higher for comorbidity patients for all comorbidities except eczema (p≤0.003). CONCLUSIONS:  For 8 comorbidities associated with endometriosis, there were significant absolute increases in health care spending after onset; for another 13, there were significant relative increases in spending. Whether these relationships reflect the diagnosis or extent of endometriosis or the pathophysiology of the disease requires further investigation.