Background <p>Hand-foot syndrome (HFS) is the most common adverse effect of capecitabine.</p> Objective <p>We aimed at evaluating the protective effect of celecoxib against capecitabine induced hand and foot syndrome in patients with colorectal cancer (CRC).</p> Methods <p>In this randomized controlled parallel study, 44 newly diagnosed patients with stage II CRC were randomly allocated into two groups; Group 1(control group; n = 22) which received 6 cycles of capecitabine-based chemotherapy (cycle is every 3 weeks) and group 2 (celecoxib group; n = 22) which received 6 cycles of capecitabine-based chemotherapy (cycle is every 3 weeks) in addition to 200&#xa0;mg of oral celecoxib twice daily for 14 days of the 3-week cycle. At baseline and after the 6th chemotherapy cycle the patients’ quality of life (QOL) was assessed using hand and foot syndrome (HFS) specific QOL questionnaire (HFS-14). Moreover, blood samples were collected in order to evaluate the serum levels of cyclooxygenase-2 (COX-2), tumour necrosis factor-alpha (TNF-α) and malondialdehyde (MDA). Data was analysed using paired and un-paired t-tests.</p> Results <p>At the end of the study and as compared to control group, celecoxib treated group showed significantly lower incidence of HFS (<i>P</i> = 0.015). Additionally, celecoxib treated group showed significant decline in the serum levels of TNF-α (<i>P</i> = 0.016) and MDA (<i>P</i> = 0.014) which was associated with non-significant difference in the serum level of COX-2 between the two groups (<i>P</i> = 0.476). Celecoxib was safe and well-tolerated throughout the study period.</p> Conclusion <p>Celecoxib may represent a potential protective agent against capecitabine induced hand and foot syndrome in patients with colorectal cancer.</p>