Background: Over a period our department experienced an unexpected high frequency of anastomotic leakages. After diclofenac was removed from the postoperative analgesic regimen, the frequency dropped. This study aimed to evaluate the influence of diclofenac on the risk of developing anastomotic leakage after laparoscopic colorectal surgery. Methods: This was a retrospective case-control study based on 75 consecutive patients undergoing laparoscopic colorectal resection with primary anastomosis. In period 1, patients received diclofenac 150 mg/day. In period 2, diclofenac was withdrawn and the patients received an opioid analgesic instead. The primary outcome parameter was clinically significant anastomotical leakage verified at reoperation. Results: 1/42 patients in the no-diclofenac group compared with 7/33 in the diclofenac group had an anastomotic leakage after operation (p = 0.018). In a multivariate regressional analysis, none of the recorded factors were significantly associated with the frequency of anastomotical leakages when diclofenac treatment was omitted from the model. Conclusions: We found an increased number of clinically significant anastomotic leakages in patients receiving oral diclofenac for postoperative analgesia. There is an urgent need to test our hypothesis in prospective randomized clinical trials and to examine whether our findings can be extended to open surgery and to other NSAIDs.