The high prevalence of nicotine dependence contributes to excess mortality in schizophrenia. Cue reactivity, or the encounter of drug-related cues or contexts, triggers craving, drug-seeking, and relapse. Prior functional magnetic resonance imaging (fMRI) research indicates that individuals with schizophrenia have blunted neural responses to rewarding stimuli in association with more severe negative symptoms. The objectives of this study are to determine if smokers with schizophrenia have altered neural reactivity to smoking cues compared with non-psychiatrically ill smokers and to evaluate the influence of negative symptoms on cue reactivity. Twenty smokers with schizophrenia and 19 control smokers underwent fMRI while viewing smoking-related and neutral cues. The primary analysis was group comparison of Smoking-Neutral contrast using whole-brain analysis (Pcorrected < .05). Smokers with schizophrenia had significantly greater baseline carbon monoxide levels and longer duration of smoking, suggesting more nicotine use. While both groups had greater brain reactivity to smoking vs neutral cues, smokers with schizophrenia had significantly decreased cue reactivity (Smoking-Neutral) compared to controls in bilateral frontal midline regions. There were significant negative correlations between negative symptoms and frontal midline reactivity. Despite greater nicotine use, smokers with schizophrenia exhibited decreased smoking cue-induced neural reactivity in frontal midline regions, suggesting that increased smoking and low cessation rates in schizophrenia are not primarily driven by responses to smoking-related cues. The finding of negative correlations between cue reactivity and negative symptoms is consistent with previous research demonstrating decreased neural responses to rewarding cues, particularly in patients with negative symptoms.