Application of the Thallium-201 quantitative analysis method to Tc-99m Sestamibi planar myocardial perfusion images results in oversubtraction of tissue crosstalk, defined as 'activity within the myocardial image, which originated outside the heart'. A modified algorithm, specific for Tc-99m Sestamibi, was applied in 60 patients and the results of quantitative analysis to estimate the risk of coronary artery disease were compared with coronary angiographic findings and with visual analysis. New crosstalk planes were generated based on the results in 20 male healthy volunteers. The results in our study group indicate a higher diagnostic accuracy when circumferential profiles are generated on the basis of maximal counts compared to mean counts. Quantitative analysis was able to predict the presence or absence of CAD as accurately as visual analysis. Odds ratios were 1.07 and 1.32 respectively (P < 0.001) for both quantitative maximal uptake and visual uptake analysis. Sensitivity of visual analysis alone was 89%, increasing to 96% with combined visual/quantitative analysis. Specificity of visual analysis decreased from 79% to 64% with combined analysis. Although only minor differences are seen, the maximal count uptake profiles were found to have additional diagnostic value compared to visual analysis alone.