Phosphoglycerate dehydrogenase (PHGDH) plays an essential role in cancer-specific metabolic reprogramming. It has been reported as a putative metabolic oncogene in several types of human malignant tumors, such as breast cancer and melanoma. To date, PHGDH expression in colorectal cancer (CRC) as well as its association with clinicopathological characteristics and prognostic implication remain undetermined. In this study, we determined the PHGDH protein expression using tissue microarray immunohistochemistry (TMA-IHC) on 193 pairs of formalin-fixed, paraffin-embedded specimens of CRC and adjacent tissues, 25 chronic colitis, 41 low-, and 19 high-grade intraepithelial neoplasia specimens, and we also determined PHGDH mRNA level using quantitative reverse transcription PCR (qRT-PCR) on additional 23 pairs of fresh CRC tissues and adjacent tissues. We found that both PHGDH mRNA and protein was highly expressed in tumor tissues in comparison with matched adjacent non-tumor tissues, and high PHGDH protein expression was correlated with advanced TNM stage (P = .038) and larger tumor (P = .001). Multivariate Cox regression analysis showed that PHGDH protein expression (HR = 2.285, 95% CI = 1.18 to 4.41, P = .014), tumor differentiation (HR = .307, 95% CI = .154 to 0.609, P = .001), and TNM stage (HR = 1.791, 95% CI = 1.125 to 2.85, P = .014) were independent prognostic factors in CRC. Kaplan-Meier survival curves and log rank test showed that high PHGDH protein expression contributed to poor outcome in CRC patients (P < .001). In conclusion, these results suggest that assessment of PHGDH expression could be useful in identifying a high-risk subgroup of CRC.