Increasing research has indicated that absent in melanoma 2 (AIM2) is aberrantly expressed in several tumor types. However, the association between AIM2 expression and clinicopathological factors or prognosis of patient with colorectal cancer (CRC) remains elusive. In the present study, we first examined the protein and mRNA expression of AIM2 in CRC cell lines by western blotting and quantitative RT-PCR (qRT-PCR). Then, we detected AIM2 expression in CRC tissue using western blotting and immunohistochemistry (IHC) respectively to evaluate its clinicopathological characteristics and prognosis in CRC. Our cytological experiments showed that there was low AIM2 expression in most of the CRC cell lines. Western blotting and IHC indicated that AIM2 expression was obviously lower in the primary CRC tissue than the adjacent normal tissue (P<0.01 and P<0.001). Clinicopathological analysis revealed that low AIM2 expression was significantly associated with some clinicopathological features such as depth of invasion (P=0.020), TNM clinical stage (P=0.013) and lymph node metastasis (P=0.026). Spearman analysis indicated that there was a negative correlation between AIM2 expression and preoperative serum carcino-embryonic antigen (CEA) levels in CRC patients (r=−0.217, P=0.009). Moreover, Kaplan-Meier analysis showed that low expression of AIM2 could lead to a significantly shorter overall survival rate (P=0.001). Cox’s proportional hazards model also indicated that the low expression of AIM2 could serve as an independent and significant prognostic factor for survival. Taken together, our findings identify AIM2 as a valuable biomarker for prognosis and a potential therapeutic target for CRC.