There is growing documentation that infants exposed to opioids and poly-substances prenatally have an increased risk of aberrant development. In Norway, there are several in-patient clinics that specialize in medically supervised detoxification for pregnant women with substance dependence in a therapeutic setting. Because there is virtually no documentation on the perinatal outcome of the infants born to mothers receiving such treatment, this study aims to investigate the perinatal outcome of children born to mothers with opioid and poly-substance dependence detoxified in a residential setting during pregnancy compared with infants born to women with substance dependence at a time when no such treatment was available. Pregnant women from two time cohorts were followed from pregnancy to birth. Birth weight, head circumference, gestational age, and neonatal abstinence syndrome (NAS) were measured in infants born to mothers detoxified in a residential setting during pregnancy and compared with infants born to mothers receiving no treatment. Both study groups had concurrent comparison groups. Infants born to mothers in residential detoxification treatment experience less prenatal drug exposure and show better perinatal outcomes on gestational age and head circumference, as well as no NAS, compared to the infants in the earlier cohort whose mothers did not receive residential treatment. No miscarriages, complications, or morbidities were associated with residential detoxification treatment. Detoxification in residential treatment can be a preferred treatment form for many pregnant women struggling with drug abuse problems and should possibly be applied to a larger extent to ensure the best possible perinatal outcome for these children.