BACKGROUND: The inflammation response is modulated by the elaborated chemokine-chemokine receptor system, which also plays an important role in the development of acute rejection (AR). In this study, we hypothesized that functional genetic variants of some of these modulatory proteins might influence the outcome of AR. METHODS: In a retrospective analysis of a cohort of heart transplanted patients (n=158), we examined eight polymorphisms in four genes implicated in this inflammatory process: RANTES, CCR5, CCR2 and CX3CR1. On the basis of timing occurrence, AR episodes (grade>or= 3A) were classified in "early" (0-3 months posttransplantation; EAR) or "late" outcomes (4-12 months posttransplantation; LAR). RESULTS: The incidences of EAR and LAR were 57.6% and 41%, respectively. Number of LAR episodes was significantly higher in subjects that have already experienced one or more EAR episodes, as compared to subjects that had no EAR (median [25%-75%]: 4 () vs. 1 [1-2.5] respectively; P<0.0001). Statistical univariate analysis showed that none of the mentioned polymorphisms were correlated with EAR or LAR. However, allele-allele association analysis showed that subjects carrying both the CX3CR1 249I allele and CCR5 No-E haplotypes were significantly at lower risk of experiencing EAR (OR=0.2 [95%-CI=0.1-0.5], P=0.001). In contrast subjects carrying both the CCR5 E haplotype and the RANTES -403A allele were significantly at higher risk to develop LAR (OR=8.1 [95%-CI=2.3-28.7], P=0.002). CONCLUSIONS: This exploratory study in heart transplantation suggests that the outcomes of EAR and LAR episodes may be influenced by genetic variant interactions such as "CX3CR1 249I*CCR5 No-E" and "CCR5 E*RANTES -403A."