Cytokines are key immune mediators and it has been suggested that cytokine gene polymorphisms affecting expression influence rejection or tolerance. This study sought to examine this hypothesis with the aim of identifying predictive genotype markers for rejection. The study group consisted of 120 consecutive first cadaveric recipient-donor pairs transplanted at a single centre, between 1994 and 1997. PCR utilising sequence-specific primers (SSP) methodology was optimised for genotyping recipient and donor DNA for the following polymorphisms: tumour necrosis factor (TNF) -alpha (-308, G/A), interleukin (IL)-10 (-1082, G/A), IL-4 (-590, C/T), transforming growth factor (TGF) -beta1 (+915, G/C). Recipient-donor pairs were divided into rejectors (n = 28) and non-rejectors (n = 92). Each group was further stratified according to number of rejection episodes and HLA-DR mismatching. Recipient-donor pairs both lacking the IL-4*T allele (recipient low producer/donor low producer) were significantly increased in the rejector group (P = 0.02). Also, the combination of recipient IL-10*A negative/donor IL-10*A positive (recipient high producer/donor low producer), was significantly decreased in multiple rejectors (P = 0.04). No significant associations were detected between TNF-alpha and TGF-beta1, and rejection. This study suggests that the combination of recipient-donor IL-4 and IL-10 genotypes may be important in renal transplantation outcome. The results appear to corroborate the protective role of both of these cytokines, possibly due to their ability to suppress inflammation. However, due to conflicting results from this and other studies, a multi-centre collaborative study may be required to determine whether cytokine genotypes are significant, independent predictors of renal allograft rejection.