Objective：This study aims to determine whether fructose Sirtuin 5（SIRT5）expression is associated with fluorine 18（18F）fluorodeoxyglucose（FDG）accumulation，glucose transporter 1（GLUTI）expression and clinical parameters in patients with colorectal cancer（CRC）. Methods：Seventy-eight patients with CRC underwent 18F-FDG combined positron emission tomography and computed tomography（PET/CT）were analyzed. The relationship between maximum standardized uptake（SUVmax）and expression of SIRT5 and GLUT1 was analyzed，and the clinical prognosis were analyzed. The effects of SIRT5 on glycolysis and HIF1α transcriptional activity in colorectal cancer cells were investigated by using CRISPR/Cas9 technique to knock-out SIRT5. Results：The expression of SIRT5 was higher in CRC tissues when compared with in para-carcinoma tissues（P < 0.01）. The prognosis was poor in patients with high SIRT5 expression（P < 0.01）. SUVmax and SIRT5 expression were higher in patients with poorly differentiated CRC than in those with well to moderately differentiated CRC（18.18±4.06 vs. 12.72±2.60，P < 0.01；2.14±0.74 vs. 1.10±0.77，P < 0.01）. There was a positive relationship between SIRT5 expression and SUVmax（Spearman correlation coefficient=0.648，P < 0.05）. Konck-out SIRT5 gene in CRC cells led to a significant decrease in GLUT1 expression，18F-FDG uptake，and HIF1α transcriptional activity. Conclusion：SIRT5 might inhibit 18F-FDG uptake via the HIF1α/GLUT1 pathway in CRC. SIRT5 might be a potential target for the treatment of CRC.