In pediatric cases requiring quantification of cerebral blood flow (CBF) using 123I-N-isopropyl-p-iodoamphetamine (123I-IMP) single-photon emission computed tomography (SPECT), arterial blood sampling is sometimes impossible due to issues such as movement, crying, or body motion. If arterial blood sampling fails, quantitative diagnostic assessment becomes impossible despite radiation exposure. We devised a new easy non-invasive microsphere (e-NIMS) method using whole-body scan data. This method can be used in conjunction with autoradiography (ARG) and can provide supportive data for invasive CBF quantification. In this study, we examined the usefulness of e-NIMS for pediatric cerebral perfusion semi-quantitative SPECT and compared it with the invasive ARG. The e-NIMS estimates cardiac output (CO) using whole-body acquisition data after 123I-IMP injection and the body surface area from calculation formula. A whole-body scan was performed 5 minutes after the 123I-IMP injection and CO was estimated by region of interest (ROI) counts measured for the whole body, lungs, and brain using the whole-body anterior image. The mean CBF (mCBF) was compared with that acquired via ARG in 115 pediatric patients with suspected cerebrovascular disorders (age 0-15 years). Although the mCBF estimated by the e-NIMS indicated a slight deviation in the extremely low- or high-mCBF cases when compared with the values acquired using the invasive ARG, there was a good correlation between the two methods (r = 0.799; p < 0.001). There were no significant differences in the mCBF values based on physical features, such as patients' height, weight, and age. Our findings suggest that 123I-IMP brain perfusion SPECT with e-NIMS is the simplest semi-quantitative method that can provide supportive data for invasive CBF quantification. This method may be useful, especially in pediatric brain perfusion SPECT, when blood sampling or identifying pulmonary arteries for CO estimation using the graph plot method is difficult.