Substance use may influence mothers' responsiveness to their infants and negatively impact the parent-infant relationship. Maternal substance use may co-opt neural circuitry involved in caregiving, thus reducing the salience of infant cues and diminishing the sense of reward experienced by caring for infants. Gaps in understanding exist with regard to the mechanisms by which substance use operates to influence mothers' processing of infant cues and how this translates to caregiving. Therefore, we examined how substance use might relate to maternal neural responses to infant cues using event-related potentials (ERPs). Substance-using (n = 29) and nonsubstance-using (n = 29) mothers viewed photographs of infant faces and heard recordings of infant vocalizations while electroencephalography was recorded simultaneously. Three specific ERP components were used to examine initial processing of infant faces (N170) and cries (N100), and attentional allocation to infant faces and cries (P300). Substance-using mothers did not discriminate facial affect at early encoding stages (N170), were generally slower to orient to infant cries (N100), showed heightened responses to neutral faces (P300), and failed to adaptively differentiate between high-distress versus low-distress cries (P300). These differences may be important to caregiving behaviors associated with the formation of mother-child attachment. Implications are discussed, as are limitations and future directions.