Objective An inflammatory response after cardiac surgery is associated with worse clinical outcomes, but recent trials to attenuate it have been neutral. We evaluated the association between systemic inflammatory response syndrome (SIRS) and mortality after transcatheter (TAVR) and surgical aortic valve replacement (SAVR) for aortic stenosis (AS) and evaluated whether diabetes influenced this relationship. Methods Patients (n=747) with severe AS treated with TAVR (n=264) or SAVR (n=483) between January 2008 and December 2013 were included and 37% had diabetes mellitus. SIRS was defined by four criteria 12-48 h after aortic valve replacement (AVR): (1) white blood cell count <4 or >12; (2) heart rate >90; (3) temperature <36 or >38° C; or (4) respiratory rate >20. Severe SIRS was defined as meeting all four criteria. The primary endpoint was 6-month all-cause mortality (60 deaths occurred by 6 months). Inverse probability weighting (IPW) was performed on 44 baseline and procedural variables to minimise confounding. Results Severe SIRS developed in 6% of TAVR patients and 11% of SAVR patients ( p=0.02). Six-month mortality tended to be higher in those with severe SIRS (15.5%) versus those without (7.4%) ( p=0.07). After adjustment, severe SIRS was associated with higher 6-month mortality (IPW adjusted HR 2.77, 95% CI 2.04 to 3.76, p<0.001). Moreover, severe SIRS was more strongly associated with increased mortality in diabetic (IPW adjusted HR 4.12, 95% CI 2.69 to 6.31, p<0.001) than non-diabetic patients (IPW adjusted HR 1.74, 95% CI 1.10 to 2.73, p=0.02) (interaction p=0.007). The adverse effect of severe SIRS on mortality was similar after TAVR and SAVR. Conclusions Severe SIRS was associated with a higher mortality after SAVR or TAVR. It occurred more commonly after SAVR and had a greater effect on mortality in diabetic patients. These findings may have implications for treatment decisions in patients with AS, may help explain differences in outcomes between different AVR approaches and identify diabetic patients as a high-risk subgroup to target in clinical trials with therapies to attenuate SIRS.