•Infants of substance-abusing mothers (ISAM) have significant growth and neurodevelopmental abnormalities. The origin of these abnormalities is unknown. We postulated that ISAM have increased sympathetic nervous system tone and altered catecholamine levels. Therefore, we measured plasma norepinephrine, epinephrine, and dopamine levels and the number and receptor affinity of β-adrenoreceptor binding sites on lymphocytes and α-adrenoreceptor binding sites on thrombocytes in 22 otherwise healthy ISAM (age, 2.1 ±0.5 months; mean±SD) and 15 healthy controls (age, 2.5 ±0.8 months). Norepinephrine levels in venous blood were 1.8-fold higher in ISAM than in control infants (6.30 ±3.85 nmol/L vs 3.55 ±2.45 nmol/L). There were no differences in plasma epinephrine or dopamine levels. There were no differences in the number of binding sites or receptor affinity for β- and α-adrenoreceptors. We conclude that ISAM have elevated circulating norepinephrine levels compared with controls. We speculate that this is associated with increased sympathetic nervous system tone in ISAM and that the absence of adrenoreceptor down-regulation may create catecholamine suprasensitivity.