Abstract: Background and purpose The tumor differentiation grade （TDG） system based on the traditional degree of differentiation was widely used. However, it had limitations such as insufficient prognostic value and uneven distribution of constituent ratios. A new grading system based on quantifying poorly differentiated clusters （PDCs） had the advantages of reproducibility and improved prognostic value. This study aimed to investigate the relationship between PDC grading and clinicopathological parameters of colorectal adenocarcinoma and to analyze the value of a new histological grading system in clinical application. Methods 445 patients with colorectal adenocarcinoma who underwent radical surgical resection from January 2015 to December 2015 at Guangdong Provincial Hospital of Chinese Medicine were retrospectively collected, including 237 males and 208 females, ranging in age from 31 to 93 years, with a median age of 64. Tumor size ranged from 0.9 to 9.0 cm （mean 4.7 cm）. There were 155 cases of left colon cancer, 112 cases of right colon cancer, and 178 cases of rectal cancer. According to the standard evaluation method, PDC was divided into three grades, and the relationship between PDC grade and other clinicopathological parameters of colorectal adenocarcinoma was analyzed. According to the World Health Organization （WHO）, TDG was divided into two grades. The distribution differences between the PDC and TDG systems were analyzed, and the improved PDC system （two grades） was re-graded to a significant part of TDG. Results Among 445 cases of colorectal adenocarcinoma, 122 cases （27.4%） were G1 grade, 126 cases （28.3%） were G2 grade, and 197 cases （44.3%） were G3 grade. PDC was positively correlated with invasion depth, lymphovascular invasion, lymph node metastasis, nerve invasion, distant metastasis stage, and tumor budding （TB）（P<0.05）, but not with gender, age, tumor site, and tumor size （P>0.05）. According to the TDG grading system, 365 cases （82.0%, the proportion was obviously high） were TDG low （TDG-L）, and 80 cases （18.0%） were TDG high （TDG-H）. The distribution of the PDC was more even than TDG. 365 cases of TDG-L were re-graded using the modified PDC grading system. The PDC grading was positively correlated with the depth of tumor invasion, lymphovascular invasion, lymph node metastasis, nerve invasion, and tumor budding in the TDG-L group （P<0.05）. Conclusions PDC was closely related to the invasive biological behavior of colorectal adenocarcinoma. Classifying colorectal adenocarcinoma with a new histological grade based on the PDC grading system was feasible, which might provide patients with more valuable prognostic information. TDG-L could be re-graded using PDC, which might be a more objective and practical prognostic classification parameter than traditional histological differentiation.