To evaluate the efficacy of long-term postoperative adjuvant chemotherapy with low-dose cisplatin (CDDP) plus 5-fluorouracil (5-FU) (CDDP/5-FU), we retrospectively examined 167 patients with squamous cell carcinoma of the esophagus who received the treatment after curative surgery (R0 resection). We classified the patients into the following three groups according to their postoperative therapies and analyzed their outcomes: a) low-dose CDDP (10 mg body(-1) day(-1) x 5 days) plus 5-FU (250-500 mg body(-1) day(-1) x 5 days) repeated every 6 months for 3 years, with an oral fluoropyrimidine (5-FU 150-200 mg body(-1) day(-1) or UFT 300-400 mg body(-1) day(-1)) administered between each treatment cycle (low-dose CDDP/5-FU group, 98 patients); b) high-dose CDDP (80 mg body(-1) day(-1) x 1 day) plus 5-FU (750-1,000 mg body(-1) day(-1) x 5 days) administered once only, followed by treatment with an oral fluoropyrimidine (5-FU 150-200 mg body(-1) day(-1) or UFT 300-400 mg body(-1) day(-1)) for 3 years (high-dose CDDP/5-FU group, 17 patients); or c) surgery alone (surgery alone group, 52 patients). The 3-year survival rates were 83.7% in the low-dose CDDP/5-FU group, 61.4% in the high-dose CDDP/5-FU group, and 62.2% in the surgery alone group; the difference between the low-dose CDDP/5-FU group and surgery alone group was significant (log-rank, p<0.05). A significantly better outcome in the low-dose CDDP/5-FU group than in the surgery alone group was associated with pStage III disease (p<0.001), pN1 lymph node metastasis (p<0.001), and lymphatic invasion (p<0.01). We conclude that long-term postoperative treatment with low-dose CDDP/5-FU is therapeutically beneficial and prolongs survival in patients with esophageal cancer who have regional lymph node metastasis or lymphatic invasion.