Evidences in rodents suggest that tacrolimus-induced post-transplant hypertension is due to upregulation of the thiazide-sensitive Na+-Cl- cotransporter, NCC. Here we analyzed if a similar mechanism is involve in post-transplant hypertension in humans. From January 2013 to June 2014 all adult kidney transplant recipients receiving a kidney allograft were enrolled into a prospective cohort study. All patients received tacrolimus as part of the immunosuppressive therapy. Six months after surgery we assessed general clinical and laboratory variables, tacrolimus trough blood levels, and ambulatory 24-hour blood pressure monitoring. Urinary exosomes were extracted to perform Western blot analysis using total and phospho­NCC antibodies. A total of 52 patients, including 17 women and 35 men, were followed. At six months after transplantation, of the 35 men, 17 developed hypertension and 18 remained normotensive, while high blood pressure was observed in only 3 out 17 women. The hypertensive patients were significantly older than the normotensive group, however there were no significant differences in body weight, history of acute rejection, renal function, and tacrolimus through levels. In urinary exosomes, hypertensive patients showed higher NCC expression (1.7 ± 0.19) than normotensive (1 ± 0.13) (P=0.0096). Also, NCC phosphorylation levels were significantly higher in the hypertensive patients (1.57 ± 0.16 vs. 1 ± 0.07; P=0.0049). Our data show that there is a positive correlation between NCC expression/phosphorylation in urinary exosomes with the development of hypertension in post-transplant male patients treated with tacrolimus. Our results are consistent with the hypothesis that NCC activation plays a major role in tacrolimus-induced hypertension.