Rett syndrome, commonly associated with mutations of the methyl CpG-binding protein 2 (MECP2) gene, is characterised by an apparently normal early postnatal development followed by deterioration of acquired cognitive and motor coordination skills in early childhood. To evaluate whether environmental factors may influence the disease outcome of Rett syndrome, we tested the effect of environmental enrichment from 4 weeks of age on the behavioural competence of mutant mice harboring a Mecp2 (tm1Tam)-null allele. Our findings show that enrichment improves motor coordination in heterozygous Mecp2+/- females but not Mecp2-/y males. Standard-housed Mecp2+/- mice had an initial motor coordination deficit on the accelerating rotarod, which improved with training then deteriorated in subsequent weeks. Enrichment resulted in a significant reduction in this coordination deficit in Mecp2+/- mice, returning the performance to wild-type levels. Brain-derived neurotrophic factor (BDNF) protein levels were 75 and 85% of wild-type controls in standard-housed and environmentally enriched Mecp2+/- cerebellum, respectively. Mecp2-/y mice showed identical deficits of cerebellar BDNF (67% of wild-type controls) irrespective of their housing environment. Our findings demonstrate a positive impact of environmental enrichment in a Rett syndrome model; this impact may be dependent on the existence of one functional copy of Mecp2.