This study was performed to confirm the antibiotic regimen during a severe invasive surgery, such as esophagectomy, with a long procedure and a large amount of normal volumes of infusion. Ten patients with esophageal cancer were enrolled in this study, and cefmetazole sodium concentrations in serum were measured during esophagectomy. The ranges of minimum inhibitory concentrations for 90% of isolates of cefmetazole sodium for microorganisms in our institutions for 8 years were investigated. The maximum concentration was 83.9 μg/mL just after the completion of infusion, and its half-life was 1.5 hours. Serum concentration of cefmetazole sodium was kept above 16 μg/mL for 4 hours during esophagectomy. It was kept above 32 μg/mL for 2.5 hours after injection. There are almost no differences in the pharmacokinetics of cefmetazole sodium between common use and during esophagectomy. In addition, additive infusion of antibiotics 4 hours after the first infusion was recommended during esophagectomy.