Resolution of many technical and immune-related issues have allowed long-term survival of baboons with life-supporting pig kidney grafts. However, episodes of hypovolemia and hypotension during the post-transplant period occur via an unexplained mechanism. It has been reported that pig renin has low reactivity on human angiotensinogen (AGT). Because the renin-angiotensin system (RAS) is vitally important in the regulation of extracellular fluid volume and blood pressure, we evaluated the activity of the RAS in baboon's post-pig kidney xenotransplantation. Kidneys from genetically-modified pigs were transplanted into 5 baboons (6 to 10 kg) that were immunosuppressed by blockade of the CD40/CD154 costimulation pathway, after excision of the native kidneys. Plasma renin, AGT (only baboon AGT could be measured), and angiotensin II levels were measured by ELISAs in (i) healthy genetically-modified pigs (n=3), healthy non-immunosuppressed baboons (n=6), and (iii) immunosuppressed baboons with pig kidney grafts. Samples were collected for up to 120 days post-transplantation. Plasma renin levels were significantly greater in healthy pigs (586±139 (SE) pg/ml) than in intact baboons (430±28 pg/ml). The plasma renin levels in baboons with pig kidney grafts were similar to values in intact baboons (367±18 pg/ml), indicating the continuing production of renin by the pig kidney grafts in absence of baboon kidneys. Plasma AGT (which reflected only baboon AGT) levels were augmented in the transplanted baboons (21±0.8 µg/ml) compared to the pre-transplant concentrations (9.9±0.8). Plasma angiotensin II levels were 16±1.3 pg/ml in intact baboons and trended lower from pre-transplant levels in the transplanted baboons (10±1.6 pg/ml). Lower plasma angiotensin II concentrations in baboons with pig kidney grafts, even in the presence of increasing plasma AGT levels, may be a consequence of reduced, but not absent, reactivity of pig renin to cleave baboon AGT. The reduced angiotensin II levels in the transplanted baboons suggest an impaired ability to elicit a robust response to hypovolemic and hypotensive episodes.