In young, healthy people the alveolar-arterial P(O(2)) difference (A-aDO(2)) is small at rest, but frequently increases during exercise. Previously, investigators have focused on ventilation/perfusion mismatch and diffusion abnormalities to explain the impairment in gas exchange, as significant physiological intra-pulmonary shunt has not been found. The aim of this study was to use a non-gas exchange method to determine if anatomical intra-pulmonary (I-P) shunts develop during exercise, and, if so, whether there is a relationship between shunt and increased A-aDO(2). Healthy male participants performed graded upright cycling to 90% while pulmonary arterial (PAP) and pulmonary artery wedge pressures were measured. Blood samples were obtained from the radial artery, cardiac output was calculated by the direct Fick method and I-P shunt was determined by administering agitated saline during continuous 2-D echocardiography. A-aDO(2) progressively increased with exercise and was related to (r = 0.86) and PAP (r = 0.75). No evidence of I-P shunt was found at rest in the upright position; however, 7 of 8 subjects developed I-P shunts during exercise. In these subjects, point bi-serial correlations indicated that I-P shunts were related to the increased A-aDO(2) (r = 0.68), (r = 0.76) and PAP (r = 0.73). During exercise, intra-pulmonary shunt always occurred when A-aDO(2) exceeded 12 mmHg and was greater than 24 l min(-1). These results indicate that anatomical I-P shunts develop during exercise and we suggest that shunt recruitment may contribute to the widened A-aDO(2) during exercise.