Background Magnetoencephalography (MEG) is an established method used to detect and localize focal interictal epileptiform discharges (IEDs). Current MEG systems house hundreds of cryogenic sensors in a rigid, one-size-fits-all helmet, which results in several limitations, particularly in children. Purpose To determine if on-scalp MEG based on optically pumped magnetometers (OPMs) alleviates the main limitations of cryogenic MEG. Materials and Methods In this prospective single-center study conducted in a tertiary university teaching hospital, participants underwent cryogenic (102 magnetometers, 204 planar gradiometers) and on-scalp (32 OPMs) MEG. The two modalities for the detection and localization of IEDs were compared. The t test was used to compare IED amplitude and signal-to-noise ratio (SNR). Distributed source modeling was performed on OPM-based and cryogenic MEG data. Results Five children (median age, 9.4 years [range, 5-11 years]; four girls) with self-limited idiopathic (n = 3) or refractory (n = 2) focal epilepsy were included. IEDs were identified in all five children with comparable sensor topographies for both MEG devices. IED amplitudes were 2.3 (7.2 of 3.1) to 4.6 (3.2 of 0.7) times higher (P < .001) with on-scalp MEG, and the SNR was 27% (16.7 of 13.2) to 60% (12.8 of 8.0) higher (P value range: .001-.009) with on-scalp MEG in all but one participant (P = .93), whose head movements created pronounced motion artifacts. The neural source of averaged IEDs was located at approximately 5 mm (n = 3) or higher (8.3 mm, n = 1; 15.6 mm, n = 1) between on-scalp and cryogenic MEG. Conclusion Despite the limited number of sensors and scalp coverage, on-scalp magnetoencephalography (MEG) based on optically pumped magnetometers helped detect interictal epileptiform discharges in school-aged children with epilepsy with a higher amplitude, higher signal-to-noise ratio, and similar localization value compared with conventional cryogenic MEG. Online supplemental material is available for this article. © RSNA, 2022 See also the editorial by Widjaja in this issue.