We studied the diagnostic accuracy of carcinoembryonic antigen (CEA) and cancer antigen 15.3 (CA 15.3) in detecting breast cancer recurrence. Biomarker follow-up determinations, made over 900 patients, were related to local-regional or distant recurrence using statistical models for longitudinal data. The diagnostic accuracy was quantified in terms of sensitivity, specificity and Youden index. The biomarkers were poorly predictive of local-regional recurrence. As for distant recurrence, the best diagnostic accuracy was obtained considering the two biomarkers jointly and combining two positivity criteria: a value above the normal limit or a difference between two consecutive measurements greater than the critical difference for at least one biomarker. A third criterion, based on within-patient comparison between follow-up determinations and a baseline, failed to improve the above result. CEA and CA 15.3 might play a role in patient monitoring during follow-up for the search of distant recurrence.