Abstract: Objective To investigate the efficacy and safety of neoadjuvant radiotherapy combined with FOLFOX4 regimen in the treatment of locally advanced rectal cancer. Methods Total 63 patients who met the inclusion criteria were randomly assigned to intensity-modulated radiation therapy (IMRT) combined with capecitabine group (control group, n=31) and IMRT combined with FOLFOX4 regimen group (experimental group, n=32). The efficacy and incidence of adverse reactions at the end of neoadjuvant therapy were evaluated. The radical operation was performed 6 weeks after neoadjuvant therapy, the pathological complete remission rate and anus preservation rate were analyzed and compared. Results The curative effect could be evaluated in all 63 patients. The total effective rate of the experimental group was 84. 4% and of the control group was 74. 2%, the total effective rate of the experimental group was higher than that in the control group, but there was no significant difference between two groups (P > 0. 05); The pathological complete remission rate of the experimental group was 34. 4%, and of the control group was 12. 9%, the rate of experimental group was higher than that in the control group, there was significant difference between two groups (P < 0. 05). The anal preservation rate of the experimental group was 81. 3%, and of the control group was 58. 1%, the rate of experimental group was higher than that in the control group, there was significant difference between two groups (P < 0. 05). The toxicity of the two groups were relatively light, with grade1 and grade2, there was no significant difference between two groups (P > 0. 05). Conclusion Intensity-modulated radiotherapy combined with FOLOFX4 regimen as neoadjuvant therapy for locally advanced rectal cancer can improve the response rate, pathologic complete response rate and anal preservation rate, not increasing the incidence of adverse reactions and complications, worthy of clinical application.