BACKGROUND. The 2001 Bethesda System (TBS 2001) introduced a new diagnostic category-normal endometrial cells in women age 40 years or older (EM ≥ 40). The objective of the current study was to determine whether there was any significant increase in the frequency with which this diagnosis was reported after the implementation of TBS 2001 and the clinical significance of this diagnosis. METHODS. All women who had a Papanicolaou (Pap) test and a diagnosis of EM ≥ 40 between January 1999 to December 2003 were identified. Follow-up included repeat Pap tests and/or surgical pathology. TBS 2001 was implemented on January 1, 2002. RESULTS. In total, 556 Pap tests with a diagnosis of EM ≥ 40 were identified, accounting for 0.52% of the 106,204 Pap tests evaluated during the study period. The incidence of EM a 40 before and after implementation of the new TBS was 0.47% and 0.61%, respectively, and showed a statistically significant difference. One hundred four patients (19%) underwent endometrial tissue sampling, including 22 patients who underwent hysterectomy (4%) and 82 patients who underwent endometrial biopsy (15%). Overall, 1 patient (2%) had significant endometrial pathology, namely, complex endometrial hyperplasia without atypia. CONCLUSIONS. A significant increase in the incidence of EM a 40 was observed with the implementation of TBS 2001. However, there was no difference in the proportion of patients that underwent endometrial tissue sampling. In addition, the incidence of clinically significant endometrial lesions associated with such a diagnosis was very low. The authors recommend that women with benign endometrial cells on Pap tests in women age 40 years or older should undergo endometrial biopsy only when additional clinical indicators are identified. © 2005 American Cancer Society.