Background: Early tumor shrinkage (ETS) has been reported as a prognostic predictor of chemotherapy for colorectal cancer. However, few studies have examined the potential of ETS in chemotherapy for pancreatic cancer. Herein, we evaluated whether ETS could be a prognostic predictor in patients treated with modified FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin) or GnP (gemcitabine plus nab-paclitaxel) for locally advanced pancreatic cancer (LAPC), as an exploratory analysis of JCOG1407, a randomized phase II selection design trial comparing modified FOLFIRINOX and GnP for LAPC. Methods: Of 126 patients enrolled in JCOG1407, 112 with measurable lesions were included in this exploratory analysis. ETS was defined as a ≥ 20% reduction in tumor diameter compared with baseline at the initial imaging assessment 6–10 weeks after initiating chemotherapy. Patients were divided into two cohorts based on their ETS status as described above: the ETS cohort that achieved ETS and the non-ETS cohort that failed to achieve ETS. The impact of ETS on overall survival (OS) was compared using multivariable Cox regression analysis in (ⅰ) the modified FOLFIRINOX group, (ⅱ) the GnP group, and (ⅲ) the overall population. Results: Herein, we included 55 patients in the modified FOLFIRINOX group and 57 in the GnP group. Notably, 14 (25.5%) and 24 (42.1%) patients achieved ETS in the modified FOLFIRINOX and GnP groups, respectively. In the modified FOLFIRINOX group, the median OS in the ETS and non-ETS cohorts was 2.5 and 1.7 years, respectively; the adjusted hazard ratio (HR) of the ETS to the non-ETS cohort for OS was 0.37 (95% confidence interval [CI], 0.15-0.93). In the GnP group, the median OS in the ETS and non-ETS cohorts was 2.0 and 1.7 years, respectively; the adjusted HR of the ETS to the non-ETS cohort for OS was 0.51 (95% CI, 0.26-1.01). In the overall population, the median OS in the ETS and non-ETS cohorts was 2.3 and 1.7 years, respectively; the adjusted HR of the ETS to the non-ETS cohort for OS was 0.45 (95% CI, 0.27-0.75). Conclusions: We noted a trend toward increased survival in patients who achieved ETS, suggesting that ETS may be a prognostic predictor in patients with LAPC treated with modified FOLFIRINOX or GnP.