Exposure to both drugs of abuse and environmental enrichment (EE) are widely studied experiences that induce large changes in dendritic morphology and synaptic connectivity. As there is an abundance of literature using EE as a treatment strategy for drug addiction, we sought to determine whether EE could remediate the effects of prenatal nicotine (PN) exposure. Using Golgi-Cox staining, we examined eighteen neuroanatomical parameters in four brain regions [medial prefrontal cortex (mPFC), orbital frontal cortex (OFC), nucleus accumben, and Par1] of Long-Evans rats. EE in adolescence dramatically altered structural plasticity in the male and female brain, modifying 60% of parameters investigated. EE normalized three parameters (OFC spine density and dendritic branching and mPFC dendritic branching) in male offspring exposed to nicotine prenatally but did not remediate any measures in female offspring. PN exposure interfered with adolescent EE-induced changes in five neuroanatomical measurements (Par1 spine density and dendritic branching in both male and female offspring, and mPFC spine density in male offspring). And in four neuroanatomical parameters examined, PN exposure and EE combined to produce additive effects [OFC spine density in females and mPFC dendritic length (apical and basilar) and branching in males]. Despite demonstrated efficacy in reversing drug addiction, EE was not able to reverse many of the PN-induced changes in neuronal morphology, indicating that modifications in neural circuitry generated in the prenatal period may be more resistant to change than those generated in the adult brain. Synapse 68:293–305, 2014. © 2014 Wiley Periodicals, Inc.