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This study was designed to investigate the effect of octreotide on side effects of immediate usage of 5-fluorouracil after colonic anastomosis.Forty male Wistar rats were randomly assigned into four groups and underwent standardized left colonic anastomosis. The rats served as control or received intraperitoneal 5-fluorouracil (20 mg/kg daily), subcutaneous octreotide (20 μg/kg daily), or both. Diarrhea and wound complications were noted during the experiment. The colonic anastomoses were assessed for healing on postoperative Day 7 by determining the anastomotic bursting pressure, performing histologic examination, and measuring the tissue hydroxyproline content, serum malondialdehyde, and nitric oxide levels. Intraperitoneal adhesions and anastomotic leakage were also noted.No statistical significant difference was found between the control and octreotide groups for each of the parameters measured. Immediate 5-fluorouracil use resulted with higher adhesion score (P= 0.002), significant depression in anastomotic bursting pressure (P= 0.0001), histopathologic score (P= 0.0001), hydroxyproline content (P= 0.0001), and increasing nitric oxide (P= 0.0001) and malondialdehyde levels (P= 0.0001) compared with the control group. Diarrhea was seen in 80 percent of the 5-fluorouracil group but in neither the control nor octreotide groups (P= 0.0001 for each comparison). However, all these parameters were ameliorated by use of concomitant octreotide and 5-fluorouracil (P= 0.019,P= 0.023,P= 0.0001,P= 0.006,P= 0.0001, andP= 0.013, respectively). In addition, diarrhea was found to be prevented (P= 0.0001).The results of this study showed that concomitant octreotide use might prevent the side effects of 5-fluorouracil, such as diarrhea, postoperative adhesion, and delaying the anastomotic healing parameters. In addition, it might reduce tissue damage and inflammation.