This study aimed to evaluate the immunoreactivity of sirtuin 1 (SIRT1) and sirtuin 2 (SIRT2) in colorectal cancer tissues using immunohistochemistry and to investigate their potential roles in the diagnosis and prognosis of colorectal cancer.Colon specimens from 104 patients diagnosed with colorectal adenocarcinoma at SBÜ Kartal Dr. Lütfi Kırdar City Hospital between 2016 and 2021 were analyzed. Immunohistochemical staining was performed to assess the immunoreactivity of SIRT1 and SIRT2. Associations between the clinicopathological parameters of colorectal cancer patients and the expression levels of SIRT1 and SIRT2 (categorized as low or high) were examined.SIRT1 expression was significantly associated with K-RAS mutations (p=0.021) but showed no significant association with N-RAS (p=0.114) or B-RAF (p=0.624) mutations. SIRT2 expression levels were significantly associated with TNM stage (p=0.043), presence of metastasis (p=0.004), K-RAS mutations (p=0.047), and N-RAS mutations (p=0.020). Co-expression of SIRT1 and SIRT2 was significantly correlated with TNM stage (p=0.041), presence of metastasis (p=0.012), and mutations in K-RAS (p=0.028) and N-RAS (p=0.022).SIRT2 expression levels were significantly correlated with TNM classification, as well as the presence of metastasis. In contrast, SIRT1 expression was not significantly associated with these parameters. Both SIRT1 and SIRT2 showed a statistically significant relationship with K-RAS mutations, highlighting their potential roles in the molecular pathology of colorectal cancer.