We studied 1,183 Papanicolaou (Pap) cytology cases (739 with normal endometrial cells [nEMCs], 423 with atypical EMCs [aEMCs], and 21 with endometrial cancer cells [EMCCs] in women 40 years or older) with histologic follow-up. Significant endometrial lesions were found in 2.7%, 18.4%, and 100% of cases with nEMCs, aEMCs, and EMCCs, respectively. Significant lesions were present in women 50 years or older with nEMCs found after day 12 of the menstrual cycle or who were postmenopausal (5.2%), but not in women with nEMCs before day 12 (0.5%) or women younger than 50 years with nEMCs after day 12 (1.6%). Our data indicate that endometrial sampling provides no clinical benefit in women (regardless of age) with nEMCs before day 12 of the menstrual cycle or women younger than 50 years with nEMCs after day 12. Endometrial sampling should be routinely performed in women with aEMCs and in women 50 years or older with nEMCs after day 12 of the menstrual cycle or who are postmenopausal.