PURPOSE: To evaluate the influence of adjuvant tamoxifen and exemestane on cognitive functioning in postmenopausal patients with breast cancer (BC). PATIENTS AND METHODS: Neuropsychological assessments were performed before the start (T1) and after 1 year of adjuvant endocrine treatment (T2) in Dutch postmenopausal patients with BC, who did not receive chemotherapy. Patients participated in the international Tamoxifen and Exemestane Adjuvant Multinational trial, a prospective randomized study investigating tamoxifen versus exemestane as adjuvant therapy for hormone-sensitive BC. RESULTS: Participants included 80 tamoxifen users (mean age, 68.7 years; range 51 to 84), 99 exemestane users (mean age, 68.3 years; range, 50 to 82), and 120 healthy controls (mean age, 66.2 years; range, 49 to 86). At T2, after adjustment for T1 performance, exemestane users did not perform statistically significantly worse than healthy controls on any cognitive domain. In contrast, tamoxifen users performed statistically significantly worse than healthy controls on verbal memory (P < .01; Cohen's d = .43) and executive functioning (P = .01; Cohen's d = .40), and statistically significantly worse than exemestane users on information processing speed (P = .02; Cohen's d = .36). With respect to visual memory, working memory, verbal fluency, reaction speed, and motor speed, no significant differences between the three groups were found. CONCLUSION: After 1 year of adjuvant therapy, tamoxifen use is associated with statistically significant lower functioning in verbal memory and executive functioning, whereas exemestane use is not associated with statistically significant lower cognitive functioning in postmenopausal patients with BC. Our results accentuate the need to include assessments of cognitive effects of adjuvant endocrine treatment in long-term safety studies.