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Background: Anastomotic leakage after rectal cancer surgery is linked to reduced survival and higher recurrence rates. While an aggravated inflammatory response may worsen outcomes, few studies have explored the combined effects of leakage and inflammation.

Methods: This is a retrospective multicenter cohort study including patients operated with anterior resection for rectal cancer in Sweden during 2014–2018. Anastomotic leakage within 12 months was exposure and primary outcome was recurrence-free survival. Mediation analysis was performed to evaluate the potential effect of systemic inflammatory response, as measured by the highest postoperative C-reactive protein (CRP) level within 14 days of surgery. Confounders were chosen using a causal diagram.

Results: Some 1036 patients were eligible for analysis, of whom 218 (21%) experienced an anastomotic leakage. At the end of follow-up at a median of 61 months after surgery, recurrence-free survival amounted to 82.6% and 77.8% in the group with and without leakage, respectively. The median highest postoperative CRP value after surgery was higher in the leakage group (219 mg/l), compared with the group without leakage (108 mg/l). Leakage did not lead to worse recurrence-free survival (HR 0.66; 95% CI 0.43–0.94), and there was no apparent effect through postoperative highest CRP (HR 1.12; 95% CI 0.93–1.29).

Conclusions: In conclusion, anastomotic leakage, with its accompanying CRP increase, was not found to be associated with recurrence-free survival after anterior resection for rectal cancer in this patient cohort. Larger, even more detailed studies are needed to further investigate this topic.