AbstractAimsThis study aimed to test whether there are sex differences in the relationship between impulsivity and amphetamine use disorder (AMP).DesignA naturalistic cross‐sectional design was used.SettingThe Tulsa 1000 study was held in Tulsa, OK, USA.ParticipantsThere were two groups in this study: AMP+ (29F, 20M) and AMP– (57F, 33M).MeasurementsThis project focuses on data related to impulsivity: UPPS‐P impulsive behavior scale and a stop signal task (SST) during functional magnetic resonance imaging (fMRI) recording. Group, sex and their interaction were compared for UPPS‐P ratings and SST fMRI and behavioral responses.FindingsAMP+ reported higher UPPS‐P positive and negative urgency scores (Ps < 0.001; r = 0.56 and 0.51) and displayed greater bilateral insula and amygdala responses across correct SST trials (Ps < 0.001, g range = 0.57–0.81) than AMP–. fMRI results indicated that AMP+ exhibited larger right anterior/middle insula, amygdala and nucleus accumbens signals during successful difficult stop trials than AMP– (Ps < 0.01; g = 0.63, 0.54 and 0.44, respectively). Crucially, two group × sex effects emerged: (a) within females, AMP+ reported larger UPPS‐P lack of premeditation scores than AMP– (P < 0.001, r = 0.51), and (b) within males, AMP+ showed greater left middle insula signals than AMP– across correct SST trials (P = 0.01, g = 0.78).ConclusionsBoth female and male amphetamine users appear to be characterized by rash action in the presence of positive and negative mood states as well as heightened recruitment of right hemisphere regions during behavioral inhibition. In contrast, planning ahead may be particularly difficult for female amphetamine users, whereas male amphetamine users may need to recruit additional left hemisphere resources during inhibitory processing.