Following The Bethesda System 2001 (TBS 2001) recommendation to report normal endometrial cells (nEMC) in women ages >or=40 years, studies have shown that endometrial (EM) sampling has increased, but detection of significant EM pathology has not increased. The cost implications of this increased EM sampling have not been specifically addressed. The aim of this study was to assess the cost effectiveness of EM sampling in women ages >or=40 years with nEMC in their Papanicolaou tests. The authors reviewed 499 cases at a large academic women's hospital where nEMC had been reported in Papanicolaou tests followed by EM tissue sampling. Relevant clinical information was obtained from cytopathology and surgical pathology reports. Data on costs of EM sampling were obtained from business offices. Of 1049 women ages >or=40 years who were shedding nEMC, 499 (48%) had follow-up EM sampling. In follow-up EM sampling, 6 cases of significant pathology (atypical complex EM hyperplasia or adenocarcinoma) were detected. Asymptomatic women totaled 350, and the total cost for EM sampling of asymptomatic patients shedding nEMC was estimated at 107,272 dollars. Three of the asymptomatic patients had significant EM pathology, but all 3 were postmenopausal. Three additional premenopausal patients with significant pathology were symptomatic with vaginal bleeding. No asymptomatic premenopausal patients shedding nEMC either before or after Day 12 of their menstrual cycle were found to have significant EM pathology in this large study of almost 500 women with nEMC in their Papanicolaou tests. The total costs, when projected nationally, for EM sampling in asymptomatic premenopausal women were highly significant. Educational discussions with clinicians in this community are underway to reduce the number of women who undergo EM sampling after Papanicolaou test findings of nEMC. Routine EM sampling of asymptomatic premenopausal women with nEMC in Papanicolaou tests is not cost-effective.