Autophagy has emerged not only as an essential repair mechanism to degrade damaged organelles and proteins but also as a major player in protection of tumor cells from multiple stresses. It was shown that autophagy gene polymorphisms are correlated with development of chronic inflammatory lesions, which represent a risk factor for colorectal tumors. In this study, we aimed to determine if ATG16L1+ 898A> G (Thr300Ala) polymorphism is associated with an increased risk of developing colorectal cancer (CRC) and to establish correlations between ATG16L1 genotypes and the major clinical and morphological parameters. We observed that subjects carrying GG genotype were at a higher risk for CRC (OR 1.99, 95% CI: 1.02–3.91, p= 0.039) when compared with the more frequent AA genotype, furthermore this was even more consistent in male subjects (OR 2.72, 95% CI: 1.11–6.63, p= 0.019) but not in female subjects (OR 1.29, 95% CI: 0.43–3.86, p= 0.652). In addition, we noticed a correlation between ATG16L1 GG genotype and tumor stage in moderately and poorly differentiated CRC cases. GG genotype carrying patients were at a higher risk for CRC (OR 5.19, 95% CI: 1.50–17.87, p= 0.002) when compared with the more frequent AA genotype. Such correlation suggests a possible role of autophagy gene polymorphisms in the development of human colorectal cancer.