Porcine bioprostheses are physiologically stenotic valves. Degenerative calcification leading to pathologic stenosis is an increasingly recognized serious late complication of mitral valve replacement with a porcine bioprosthesis. Hemodynamic differentiation of pathologic from physiologic stenosis is important for identification of porcine bioprosthetic valve dysfunction. In 42 patients with a normal Hancock porcine bioprosthesis (standard model, sizes 27 to 33 mm), mean diastolic flow (65 to 461 ml/s), mean gradient (2.0 to 13.4 mm Hg) and effective orifice area (1.1 to 4.4 cm2) were determined at rest, during epicardial pacing (90, 110 and 130/min) and with isoproterenol infusion. A statistically significant increase in mean gradient occurred with increases in flow and decreases in valve size (p < 0.05). Effective orifice area increased significantly as flow rate increased and as valve size increased (p < 0.05). These measurements were compared with those in 16 patients with pathologically confirmed porcine bioprosthetic valve stenosis: 8 patients with reoperation (1.1% per patient-year) 3 to 8.5 years after mitral valve replacement and 8 previously reported abnormal cases. Stenotic failure rate was inversely related to valve size (2.1, 1.4, 0.5 and 0% per patient-year for sizes 27 to 33 mm). Stenotic and normal bioprostheses were not accurately differentiated on the basis of a single value for gradient or effective orifice area. A mathematical model that related flow to the square root of the mean gradient allowed complete separation of stenotic from normal prosthetic valve function, after valve size was accounted for and normal confidence limits were established (r = 0.74 to 0.94, sizes 27 to 33, p < 0.0001). The effective orifice area-flow relation did not provide accurate differentiation of abnormal from normal function. Thus, normal mitral bioprostheses have significant transvalvular gradients whose magnitude depends on flow. Risk of stenotic failure is increased in the smaller valves, which have a larger gradient at implantation. Differentiation of pathologic from physiologic stenosis cannot be made on the basis of a single value for gradient or effective orifice area. Accurate hemodynamic differentiation is achieved by relating mean gradient to mean diastolic flow rate and valve size.