OBJECTIVE. Young infants with Down syndrome have an increased occurrence of several well-known medical conditions such as congenital heart and gastrointestinal disease. The aim of this study was to establish consequences like hospitalization and medication use rates and to determine their possible influence on early neurodevelopment. PATIENTS AND METHODS. This study compared 2 years of thyroxine treatment with placebo in 196 neonates with Down syndrome who were included in a previously reported randomized clinical trial. Parents were interviewed about comorbidity, hospitalization, and medication use at random assignment and regularly thereafter. Data were cross-checked with discharge letters when available. The influence of comorbidity on neurodevelopment at 2 years old (Bayley Scales of Infant Development II) was determined by stepwise multiple linear-regression analysis. RESULTS. Before trial entry, 163 infants with Down syndrome had been admitted to hospital for an average of 14.01 days, whereas during the trial, 95 of 181 infants who completed the trial were hospitalized for an average 19.75 days. Main hospitalization reasons during the trial were lung/airway and congenital heart and gastrointestinal disease. The 48 infants operated on for heart or gastrointestinal disease accounted for 1401 of the total number of 1876 hospital admission days during the trial and for 33 of 62 admissions for lung/airway infection. During their second year of life, ∼60% of the infants were prescribed drugs, mostly antibiotics and pulmonary. Regression analysis showed infantile spasms, “other” central nervous system disease, and gastrointestinal disease necessitating surgery to be associated with greater developmental age delays at 24 months old (mental: 6.87, 3.52, and 1.69 months; and motor: 3.59, 2.54, and 1.68 months, respectively). CONCLUSIONS. Hospital admission and medication use rates in young infants with Down syndrome are still very high, mainly because of congenital heart and gastrointestinal disease and acquired respiratory disease. Central nervous system disease and gastrointestinal disease necessitating surgery were independently associated with a worse developmental outcome.