Objectives: The purpose of this study was to assess the value of routine follow-up procedures during uterine cancer surveillance and the corresponding cost throughout a 20-year period at a single medical institution. Methods: We sought to determine which surveillance method (CA-125, imaging, physical examination or vaginal cytology) detected the highest number of patient recurrences and the corresponding cost vis-à-vis the number of identified progressive disease cases. Results: Serial imaging detected the highest number of progressive disease cases but the cost was rather high (USD 17,174 per patient recurrence), whereas CA-125 testing was the least expensive (USD 6,810 per patient recurrence). We also found that those with a variant histology [for example, adenosquamous and uterine papillary serous carcinoma (p < 0.001) and advanced (III/IV) disease stage (p = 0.001)] were associated with an unfavorable progression-free interval. Conclusions: In the present investigation, serial imaging detected the highest number of progressive disease cases, although no single surveillance method was associated with a sensitive recurrent disease detection rate. Nevertheless, the CA-125 assay appeared to be the most cost-effective method in following patients with epithelial uterine malignancies. Thus, in the context of high-risk disease, a combination of procedures may still be necessary for optimal uterine cancer patient follow-up.