We herein report the findings of two patients with small cell carcinoma of the esophagus (SCEC) who were treated with alternating chemotherapy using cisplatin and etoposide (PVP), and cyclophosphamide, adriamycin or epirubicin, and vincristine (CAV). Patient 1 was a 61-year-old woman with SCEC. Her serum level of pro-gastrin-releasing peptide (Pro-GRP) was elevated (79.8 pg/ml; normal range <46.0 pg/ml). The patient underwent an esophagectomy following PVP/CAV-therapy. Six months later her serum level of Pro-GRP became elevated, and multiple metastases to the liver and lung were detected. Two courses of PVP/CAV-therapy were performed, and these metastatic foci almost completely disappeared. The serum level of Pro-GRP was in the normal range. One year after surgery, multiple brain metastases and recurrence of liver metastases were detected, then the serum level of Pro-GRP became re-elevated. Two courses of PVP/CEV-therapy were performed, and the metastases to the brain and liver decreased in size. However, the brain metastases relapsed, and the patient died 21 months after the diagnosis. Patient 2 was treated with two courses of preoperative PVP/CAV-therapy; however, the patient died of multiple liver metastases 17 months after the diagnosis. In six previously documented patients and the two present patients who were treated with PVP/CAV-therapy, the primary or metastatic foci of SCEC decreased in size, and the mean survival of the patients was 19 months. In conclusion, PVP/CAV alternating chemotherapy is beneficial for prolonging the survival of SCEC patients; however, new chemotherapeutic modalities are still needed to further improve the prognosis of SCEC patients. Furthermore, the level of serum Pro-GRP in patients with SCEC may be both a diagnostic marker and a therapeutic monitor.