Using psychophysical studies, the authors have evaluated the effectiveness of various strategies for compensating for physical degradations in SPECT imaging. The particular application was Ga-67-citrate imaging of mediastinal tumors, which was chosen because Ga-67 is a particularly challenging radionuclide for imaging. The test strategies included compensations for nonuniform attenuation, distance-dependent spatial resolution, and scatter applied in various combinations as part of iterative reconstructions with the rescaled block iterative–expectation maximization (RBI-EM) algorithm. The authors also evaluated filtered backprojection reconstructions. Strategies were compared on the basis of human-observer studies of lesion localization and detection accuracy using the localization receiver operating characteristics (LROC) paradigm. These studies involved hybrid images which were obtained by adding the projections of Monte Carlo-simulated lesions to disease-free clinical projection data. The background variability in these images can provide a more realistic assessment of the relative utility of reconstruction strategies than images from anthropomorphic digital phantoms. The clinical datasets were obtained using a GE-VG dual-detector SPECT system with CT-estimated attenuation maps. After determining a target lesion contrast, they conducted pilot LROC studies to obtain a near-optimal set of reconstruction parameters for each strategy, and then conducted the strategy comparison study. The results indicate improved detection accuracy with RBI-EM as more compensations are applied within the reconstruction. The relative rankings of the test strategies agreed in most cases with those of previous studies that employed simulated projections of digital anthropomorphic phantoms, thus confirming the findings of those studies.