The purpose of this study was to validate the use of the circular harmonic transform (CHT) algorithm for quantitative single-photon emission computed tomography (SPECT) with isotopes technetium-99m (99mTc) and indium-111 (111In) under clinically relevant conditions. Phantom studies were the principal tools used. Volumes of fillable organs within a tissue-equivalent anthropomorphic phantom were determined over a wide range (145-1960 ml) to within 6% by using a thresholding technique. Additionally, phantom studies with nonuniform activity distributions were made. These included a background of activity and hot as well as cold lesions. The hot lesion was computed to within 12% (111In) and 7.7% (99mTc), and contrast in the cold lesion was approximately 70% for both isotopes. The CHT algorithm incorporates the energy-distance relation (EDR) which minimizes the degrading effects of attenuation, scatter, collimator blur and poor statistics.