Deficits in the computational processes of reinforcement learning have been suggested to underlie addiction. Additionally, environmental uncertainty, which is encoded in the anterior cingulate cortex (ACC), modulates reward prediction errors (RPEs) during reinforcement learning and exacerbates addiction. The present study tested whether and how the ACC would have an essential role in drug addiction by failing to use uncertainty to modulate the RPEs during reinforcement learning. In Experiment I, we found that the ACC/medial prefrontal cortex (MPFC) did not modulate RPE learning according to uncertainty in smokers. The effect of uncertainty × RPE in the ACC/MPFC was correlated with the learning rate of RPEs and the duration of nicotine use. Experiment II demonstrated that serotonin, but not dopamine, receptor mRNA expression significantly decreased in the ACC of the nicotine exposed compared to the control rats. Furthermore, there was a positive correlation between learning rate and serotonin receptor mRNA expression in the ACC. Therefore, all present results suggest that impairments in uncertainty modulation in the ACC disrupt reinforcement learning processes in chronic nicotine users and contribute to maladaptive decision-making. These findings support interventions for pathological decision-making in drug addiction that strongly focus on the serotonin system in ACC.