Purpose Pathologic response to neoadjuvant chemotherapy is a prognostic factor in many cancer types. However, the existing evaluative criteria are deficient. We sought to prospectively evaluate the total iodine uptake derived from dual-energy computed tomography (DECT) in predicting treatment efficacy and progression-free survival (PFS) time in gastric cancer after neoadjuvant chemotherapy. Methods From October 2012 to December 2015, 44 patients with locally advanced gastric cancer were examined with DECT 1 week before and three cycles after neoadjuvant chemotherapy. The percentage changes in tumor area (%ΔS), diameter (%ΔD), and density (%ΔHU) were calculated to evaluate the WHO, RESCIST, and Choi criteria. The percentage changes in tumor volume (%ΔV) and total iodine uptake of portal phase (%ΔTIU-p) were also calculated to determine cut-off values by ROC curves. The correlation between the different criteria and histopathologic tumor regression grade (Becker score) or PFS were statistically analyzed. Results Forty-four patients were divided into responders and non-responders according to 43.34% volume reduction (P = 0.002) and 63.87% (P = 0.002) TIU-p reduction, respectively. The %ΔTIU-p showed strong (r = 0.602, P = 0.000) and %ΔV showed moderate (r = 0.416, P = 0.005), while the WHO (r = 0.075, P = 0.627), RECIST (r = 0.270, P = 0.077) and Choi criteria (r = 0.238, P = 0.120) showed no correlation with the Becker score. The differences in PFS time between the responder and non-responder groups were significant according to %ΔTIU-p and Choi criteria (P = 0.001 and P = 0.013, respectively). Conclusions The TIU-p can help predict pathological regression in advanced gastric cancer patients after neoadjuvant chemotherapy. In addition, the %ΔTIU-p could be one of the potentially valuable predictive parameters of the PFS time.