The purpose of this study was to quantify circulating tumor cells (CTCs) in advanced gastric cancer (AGC) patients, and to demonstrate the role of CTCs in cancer therapy. This study investigates the hypothesis that CTCs can predict clinical outcomes in patients with AGC. From November 2007 to June 2009, 52 patients with AGC were enrolled into a prospective study. The chemotherapy regimen was an S-1-based regimen (S-1 with or without cisplatin) or paclitaxel. CTCs of whole blood at baseline, 2 weeks, and 4 weeks after initiation of chemotherapy, were isolated and enumerated using immunomagnetics. Patients with > or =4 CTCs at 2-week points and 4-week points had a shorter median progression-free survival (PFS) (1.4, 1.4 months, respectively) than those with the median PFS of <4 CTCs (4.9, 5.0 months, respectively) (log-rank test; P < 0.001, P < 0.001, respectively). Patients with > or =4 CTCs at 2-week points and 4-week points had shorter median overall survival (OS) (3.5, 4.0 months, respectively) than those with the median PFS of <4 CTCs (11.7, 11.4 months, respectively) (log-rank test; P < 0.001, P = 0.001, respectively). In conclusion, this study demonstrates that CTC measurement may be useful as a surrogate marker for determining response to S-1-based or paclitaxel regimens in AGC.