Background: The colorectal cancer (CRC) tumorigenesis is driving by genetic alterations leading to changes in protein expression such as p53. The p53 is frequently expressed in CRC and its association with clinicopathological features is still controversial. Moreover, accumulated evidence suggests that both p53 and nuclear exporter protein, exportin 1 (XPO1), are working in reciprocal manner may lead to loss of p53 nuclear localization and enhance cancer progression through hyperactive nuclear export. Accordingly, the present study aimed to evaluate the expression of p53 in CRC Yemeni patients and to explore the association between the p53 and XPO1 coexpression in relation to clinicopathological features. Methods: A series of 40 formalin fixed paraffin embedded (FFPE) tissue blocks taken from CRC patients that diagnosed as adenocarcinoma were prospectively collected and then analyzed for p53 and XPO1 expression by immunohistochemistry (IHC). The patients and tumor clinicopathological characteristics were retrieved from the histopathology reports and the P value <0.05 were considered statistically significant. Results: The p53 expression was observed in 60% (24/40) of CRC tumor samples. Significantly, the p53 expression was noted in 72.4% (21/29) of the left side compared to 27.3% (3/11) of the right side colon tumors (P=0.014). Furthermore, p53 expression was positively and significantly correlated with well-but not moderate-or poorly-differentiated tumors (P=0.023). No significant difference was observed between the p53 expression and age, gender and tumor size. Regarding the XPO1 expression, the p53 expression didn't show an association with XPO1 expression. The coexpression of p53 and XPO1 analysis revealed that 100% (11/11) tumors with negative p53 and positive XPO1 coexpression was noted with lymph node metastasis with significant difference (P=0.003) and more frequently observed in moderate-or poorly-differentiated tumors. Conclusions: The loss of p53 accompanied with increased XPO1 expressions was associated with the progression of histopathological features of CRC Yemeni patients. Further studies are needed to elucidate the p53 genetic mutations in relation to the XPO1 coexpression in CRC prognosis.