Cannabis can induce transient psychotic and anxiety symptoms and long-lasting disorders. The acute psychoactive effects of its main active ingredient, (-)-trans-Δ9-tetrahydrocannabinol (Δ9-THC), may be modulated by previous cannabis exposure. Secondary data analyses tested whether modest previous cannabis exposure modulated the acute effects of Δ9-THC on attentional salience and emotional processing and their neurophysiological substrates. Twenty-four healthy men participated in a double-blind, randomized, placebo-controlled, repeated-measures, within-subject, Δ9-THC challenge study using fMRI. Compared with nonusers (NUs; n = 12; <5 lifetime cannabis joints smoked), abstinent-modest cannabis users (CUs; n = 12; 24.5 ± 9 lifetime cannabis joints smoked) showed less efficient attentional salience processing and recruited different/additional brain areas to process attentional salient and emotional stimuli (all ps ≤ .01). The Δ9-THC challenge disrupted attentional salience and emotional-processing-related brain activity and induced transient anxiety and psychotic symptoms (all ps ≤ .02). However, Δ9-THC-induced psychotic symptoms and attentional salience behavioral impairment were more pronounced in NUs compared with CUs (all ps ≤ .04). Also, NUs under Δ9-THC shifted toward recruitment of other brain areas to perform the tasks. Conversely, CUs were less affected by the acute challenge in an exposure-dependent manner, showing a neurophysiological pattern similar to that of NUs under placebo. Only in NUs, Δ9-THC-induced psychotic symptom and cognitive impairment severity was associated with a more pronounced neurophysiological alteration (all ps ≤ .048). In conclusion, CUs displayed residual effects of cannabis exposure but more blunted responses to the acute symptomatic, behavioral, and neurophysiological effects of Δ9-THC, which were more marked in NUs. (PsycINFO Database Record (c) 2018 APA, all rights reserved).