Objective@#To detect the level of peripheral blood UL16 binding protein 2 (ULBP2) in patients with colorectal cancer, and study its value on early diagnosis and prognosis evaluation.@*Methods@#Eighty patients with colorectal cancer (colorectal cancer group) and 60 healthy subjects (healthy control group) from May 2016 to May 2019 in Affiliated Dongfeng Hospital, Hubei University of Medicine were selected. Serum expression level of ULBP2 was detected by enzyme-linked immunosorbent assay. The diagnostic efficacy of serum ULBP2 in colorectal cancer was evaluated by receiver operating characteristic (ROC) curve. The influencing factors of survival in patients with colorectal cancer were analyzed by Cox regression model. Kaplan-Meier method was used for drawing the survival curve, and log-rank test method was used for comparison.@*Results@#The serum ULBP2 level in colorectal cancer group was significantly higher than that in healthy control group: (85.52 ± 12.18) ng/L vs. (66.20 ± 8.28) ng/L, and the serum ULBP2 level of stage Ⅰ to Ⅱ in colorectal cancer group was also significantly higher than that in healthy control group: (76.44 ± 7.56) ng/L vs. (66.20 ± 8.28) ng/L, and there were statistical differences (P<0.05). ROC curve analysis result showed that the optimal cut off value of serum ULBP2 for colorectal cancer diagnosis was 79.53 ng/L, and area under curve (AUC) was 0.869, with a sensitivity of 73.75% and a specificity of 91.67%; the optimal cut off value of serum ULBP2 for stage Ⅰ to Ⅱ colorectal cancer diagnosis was 71.86 ng/L, and AUC was 0.827, with a sensitivity of 78.57%, and a specificity of 78.33%. According to the median serum ULBP2 level, the patients were divided into ULBP2 high expression (ULBP2>85.52 ng/L, 38 cases) and ULBP2 low expression (42 cases). The serum expression level of ULBP2 was related to lymph node metastasis and tissue differentiation (P < 0.05). Univariate Cox regression analysis result showed that lymph node metastasis, distant metastasis, tissue differentiation and serum ULBP2 were risk factors of poor prognosis in patients with colorectal cancer (P<0.01 or <0.05); multivariate Cox regression analysis result showed that serum ULBP2 was the independent risk factor of poor prognosis in patients with colorectal cancer (HR = 0.194, 95% CI 0.077 to 0.490, P = 0.001). The median survival time in patients with serum ULBP2 high expression was significantly shorter than that in patients with serum ULBP2 low expression (28 months vs. 50 months), and there was statistical difference (P<0.05).@*Conclusions@#Serum ULBP2 can be used as an indicator for early diagnosis and prognostic evaluation in patients with colorectal cancer.