BACKGROUND: Growth failure and undernutrition complicate the clinical course of girls with Rett syndrome (RTT). These abnormalities are, in part, the consequence of oral motor dysfunction and inadequate dietary intake. OBJECTIVE: To determine whether gastrostomy placement for nutritional therapy alters the natural history of growth failure and undernutrition in RTT. HYPOTHESIS: We hypothesized that gastrostomy placement for nutritional therapy reverses the decline in height, weight, and body mass index (BMI) z scores in RTT. METHODS: Standard stadiometric and anthropometric measures were obtained to derive height, weight, and BMI z scores and estimates of fat-free mass (FFM) and body fat in a cohort of girls (n = 92) with RTT before and after gastrostomy placement. Methyl-CpG-binding protein 2 (MECP2) mutations and the presence or absence of a fundoplication were recorded. RESULTS: The differences in height (n = 73), weight (n = 81), and BMI (n = 81) z score slopes before and after gastrostomy placement were 1.31 + 2.06 (P < 0.001), 2.38 +/- 3.18 (P < 0.001), and 3.25 +/- 3.32 (P < 0.001), respectively. FFM and body fat (n = 43) increased after gastrostomy by 41 +/- 27 g/cm height (P < 0.001) and 7.5% +/- 5.7% body weight (P < 0.001), respectively. The differences in height, weight, and BMI z score slopes were similar regardless of the age at which the gastrostomy was placed. The differences in height, weight, and BMI z score slopes, as well as the change in FFM and body fat deposition after gastrostomy placement, did not differ between those who did or did not have a fundoplication and among the classes of MECP2 mutations. CONCLUSION: Gastrostomy placement for aggressive nutritional therapy favorably altered the natural history of growth failure and undernutrition in RTT, but did not restore height and weight z scores to birth values, regardless of the age at which surgery occurred and in the presence or absence of a fundoplication.