Background. Diastolic hypertension after renal transplantation leads to significant chronic morbidity and mortality. Recently, calcineurin phosphatase inhibition by cyclosporine or tacrolimus has been postulated to lead to diastolic hypertension through the induction of transforming growth factor-β (TGF-β) and resultant endothelin-mediated renal arteriolar vasospasm. Methods. To investigate this hypothesis in humans, the allografts of 40 stable renal allograft recipients were biopsied 2 to 3 years after transplantation. Both cyclosporine and tacrolimus patients were included. Biopsies were divided and processed for histology and RNA extraction. RNA was then converted to cDNA and evaluated by semiquantitative polymerase chain reaction (actin-standardized, high-performance liquid chromatography- quantitated) for TGF-β, endothelin, and renin transcription. Inflammatory cytokine gene transcription was also evaluated. Blood pressure was measured during the clinic check-in before biopsy. Variables were evaluated by Spearman rank correlation coefficient (r(s)) analysis. Results. Diastolic hypertension was prevalent in the study population, with 40% of individuals having diastolic pressure>90 mmHg. TGF-β and endothelin transcription were detected in 88% of biopsies studied, and renin transcription was detected in 91%. Intragraft transcription of TGF-β (r(s)=0.61, P=0.0003) and endothelin (r(s)=0.43, P=0.0188) was strongly correlated with increasing transcription intragraft renin. In turn, renin transcription was strongly correlated with increasing diastolic blood pressure (r(s)=0.55, P=0.0015). Histological correlation of fibrosis score did not predict the degree of hypertension, nor did it correlate with TGF-β transcription. Inflammatory cytokine transcription was not related to renin transcription or diastolic hypertension but was correlated with histological evidence of immune graft injury. Conclusions. These data support the hypothesis that posttransplant diastolic hypertension is a result of TGF-β-induced, endothelin-mediated arteriolar vasoconstriction and subsequent activation of the renin- angiotensin pathway. These effects are independent of immune-mediated graft injury.