Objective: In the current study, we explored the neural substrate for acute effects of guanfacine extended release (GXR) on inhibitory control in school-aged children with attention deficit hyperactivity disorder (ADHD), using functional near-infrared spectroscopy (fNIRS). Methods: Following a GXR washout period, 12 AD HD children (6-10 years old) performed a go/no-go task before and 3 h after GXR or placebo administration, in a randomized, double-blind, placebo-controlled, crossover design study. In the primary analysis, fNIRS was used to monitor the right prefrontal cortical hemodynamics of the participants, where our former studies showed consistent dysfunction and osmotic release oral system-methylphenidate (OROS-MPH) and atomoxetine hydrochloride (ATX) elicited recovery. We examined the inter-medication contrast, comparing the effect of GXR against the placebo. In the exploratory analysis, we explored neural responses in regions other than the right prefrontal cortex (PFC). Results: In the primary analysis, we observed no significant main effects or interactions of medication type and age in month (two-way mixed ANCOVA, Fs < 0.20, all ps > .05). However, in the post-hoc analysis, we observed significant change in the oxy-Hb signal in the right angular gyrus (AG) for inter-medication (one sample t -test, p < 0.05, uncorrected, Cohen's d = 0.71). Conclusions: These results are different from the neuropharmacological effects of OROS-MPH and ATX, which, in an upregulated manner, reduced right PFC function in ADHD children during inhibitory tasks. This analysis, while limited by its secondary nature, suggested that the improved cognitive performance was associated with activation in the right AG, which might serve as a biological marker to monitor the effect of GXR in the ADHD children., Competing Interests: This study was funded by Shionogi & Co., Ltd. and Takeda Pharmaceutical Company Limited. The funders were involved in the design of the study and reviewed the manuscript for publication but had no role in conducting the study: collection, management, and analysis. YM reported receiving lecture fees from Nobelpharma Co., Ltd., Eli Lilly Japan K.K., Shionogi & Co., Ltd., and Takeda Pharmaceutical Company Limited. TY reported receiving a research grant from Eisai Co., Ltd. And lecture fees from Novartis Pharma K.K. ID reported receiving a research grant from Saizeriya Co., Ltd., Nichirei Corporation, Kasugai Seika Co., Ltd., and Shiseido Company. Limited. AM was a full-time employee of Hitachi, Ltd. and holds stock in Hitachi, Ltd. and Company. SS is a full-time employee of Hitachi, Ltd. YM, ID, SS, and AM have a licensed patent (WO2017142732, WO2016189955, and US 10,835,169 B2) outside of the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer MY declared a past co-authorship with the authors TI, TT, TY, ID, and YM to the handling Editor., (Copyright © 2021 Ikeda, Inoue, Tanaka, Hashimoto, Sutoko, Tokuda, Kyutoku, Maki, Yamagata, Dan and Monden.)