Background: For Stage II/III rectal cancer patients, curative resection is the primary treatment, prescribing of postoperative adjuvant chemotherapy (PAC) is regarded as a standard therapy. The interval between surgery and the initiation of PAC is usually within 8 weeks. However, the optimal cut-off is still controversial. This study aimed to explore the impact of extremely early initiation of PAC for II/III rectal cancer. Methods: Patients with Stage II/III rectal cancer treated from January 2013 to December 2015 were retrospectively collected at the Department of Tongji Hospital. According to the starting point of PAC, patients were categorized into two groups: extremely early group (The interval of PAC ≤ 2 weeks) and normal group (The interval of PAC within 3 - 5 weeks). For the sake of evaluating the effectiveness of different intervals, Overall Survival rate (OS), Progress-Free Survival rate (PFS) and Recurrence or Metastasis Rate (RMR) were analyzed, as well as the Quality of Life Score. To estimate the safety of the extremely early PAC, we evaluated the first post chemotherapy adverse reactions and defecation ability, and analyzed the variance laboratory indexes around the first postoperative adjuvant chemotherapy. Results: A total of 267 patients were included in this study. Compared to normal group (192 cases), extremely early group (75 cases) of patients attained a better tendency of OS and PFS, although there were no significant statistical differences (OS: P = 0.0930; PFS: P = 0.1058). However, the RMR was significant lower (P = 0.0452) and the Quality of Life Score was significant higher (P = 0.0090) in extremely early group. Multivariate analysis also showed that extremely early group had better defecation ability (P = 0.0149) and less side reactions of post chemotherapy, such as vomiting (P < 0.0001), diarrhea (P = 0.0494) or constipation (P = 0.0054),meanwhile, got a higher level of inflammatory cells (P < 0.0001) and a worse liver function (P = 0.0020) before first chemotherapy. Conclusion: For Stage II/III rectal cancer patients, extremely early to start PAC not only might be effectively prolonging the survival, but indeed decrease the tumor-related recurrence risk, increase the quality of life and decrease chemotherapy- associated adverse reactions. Meanwhile, appropriately controlling of inflammatory cells and protecting the liver function should be of concern to ensure the safety of early initial stage