Animal studies have suggested that the nonisomeric N3S triamide mercaptide ligand, 99mTc mercaptoacetyltriglycine (MAG3), may provide a satisfactory 99mTc-labeled replacement for 131I hippurate (OIH). Sequential 30-min [99mTc]MAG3 (5-10 mCi) and [131I]OIH (300 microCi) imaging studies were performed in ten normal volunteers in order to compare the image quality, renal excretion, blood clearance, and time to peak height of the renogram curve. In addition, [99mTc] MAG3 (5 mCi) and [131I]OIH (150 microCi) were administered simultaneously in eight volunteers for comparison of 180-min blood and plasma clearances and urine excretion. In the sequential imaging studies, the blood clearance of [99mTc]MAG3 was more rapid than [131I]OIH with a mean clearance of 1.30 l/min compared with 0.88 l/min for [131I]OIH (p less than 0.05). Seventy-three percent of the injected dose of the MAG3 was excreted by 30 min compared with 66.8% for [131I]OIH. Whole kidney and cortical renogram curves showed no significant difference in the time to peak height for MAG3 and [131I]OIH. In all subjects, the quality of the [99mTc]MAG3 images were clearly superior to [131I]OIH. Following simultaneous injection, blood and plasma clearances for [131I]OIH were more rapid than MAG3 when determined for multiple time intervals from 0-30 to 0-180 min (p less than or equal to 0.05). The 0-30-min clearances of MAG3 and [131I]OIH were only slightly greater than the 0-180-min clearances and can be used to obtain valid comparisons of the two agents. As in the sequential study, 30-min urine excretion was greater for MAG3 than [131I]OIH (73.1 compared with 69.6%) but the difference was not statistically significant. Although the differences in the MAG3 clearances following sequential and simultaneous administration are not satisfactorily explained, the fact that both clearances were rapid, the MAG3 and OIH renogram curves were quite similar, and 30-min urine excretions of MAG3 and OIH were essentially identical suggests that MAG3 may become a 99mTc replacement for [13I]OIH and further clinical evaluation is warranted.