Aims Interleukin- (IL-) 6 is a pleiotropic cytokine with effects on the acute phase response, inflammation, and vascular function. A G to C polymorphism has been described at position −174 in the promoter region of the IL-6 gene. We investigated the influence of this polymorphism on the development of cardiac transplant related coronary vasculopathy (CV). Methods Sequence specific polymerase chain reaction identified the −174*G/C allele for 116 cardiac transplant recipients. Coronary disease was identified by routine surveillance post-transplant coronary angiography. Results Prevalence of the −174*G/C polymorphism was different between the transplant and control cohorts; *CC 27.6%, *CG 45.7%, and *GG 26.7% vs. 13.2%, 44.1% and 42.7% respectively ( p = 0.004). Median time to the first diagnosis of CV was different between the 3 alleles; *CC 2.8 years (2.0–4.0); *CG 3.9 years (2.1–4.5); *GG 5.3 years (3.2–6.1) ( p = 0.05). By Kaplan-Meier survival analysis C homozygotes developed CV significantly earlier than the other cohorts ( p = 0.035). At 5 years 100% of C homozygotes had evidence for CV. G homozygotes had a more gradual onset of CV with an approximate 60% prevalence at 5 years. *CC genotype was the most predictive risk factor for CV development (Hazard ratio 4.2 (95% CI 1.3–12.9); p = 0.014). Increasing donor age was also significant (Hazard ratio 1.04 (95% CI, 1.0–1.08); p = 0.023). Conclusions Polymorphism at position −174 within the promoter region of the IL-6 gene may be an important risk factor for cardiac transplant related coronary vasculopathy. This may improve patient selection and allow tailored immunosuppressive treatment.