OBJECTIVES To determine the natural history of infant gastroesophageal reflux disease (GERD) with esophagitis, we periodically analyzed symptoms and biopsies during 1 yr in 19 infants randomly assigned to placebo in a pharmacotherapy study. METHODS One hundred infants who were referred during 1994-1999 for GERD, were unresponsive to 2-wk life-style measures, and manifested morphometric reflux esophagitis, were assigned at random to one of four treatment arms. This analysis examines the 19 (ages 2.8-6.0 months) assigned to placebo who returned for initial follow-up. SYMPTOMS and esophageal biopsy were assessed at baseline and 2, 4, 6, and 12 months. At any visit with both symptoms and biopsy unimproved, infants were "rescued" to open label active drug. RESULTS By 12 months, 10/19 completed without rescue; the 9 others withdrew (3) or required pharmacotherapy (6). SYMPTOMS Among the 10 nonrescued completers, parents' global score rated 9 "completely well," and 1 "improved." Comparing 12-month symptoms to baseline symptoms in the 10 completers, fewer reported regurgitation >3/day, >1 Tbsp, or that was uncomfortable; crying >1 h/d, or during or after feeds; or arching spells or abnormal hiccups (p < 0.05, chi(2)). Biopsy: None of the 10 ever had normal biopsies (basal cell layer <25% and papillary height <53% of epithelial thickness). One had normal papillary height, but abnormal basal thickness. Five others had normal basal thickness, but all five of them had abnormal papillary height. CONCLUSION Although symptoms improved in more than half of the infants with reflux esophagitis followed longitudinally for 1 yr without pharmacotherapy, histology remained abnormal.