A cohort of 917 Down syndrome (DS) children born in Italy between 1978 and 1984 was studied for survival through the age of 8 years. The highest mortality occurred in the first month of life (7.9%); survival was about 80% at 1 year, 78% at 2 years, and 76% at 5 years, with small decreases thereafter. At the univariate analysis, survival was lower for subjects with congenital heart disease (CHD), birth weight less than 2,500 g, parity of 3 or plus, maternal age greater than or equal to 35 years, and for those born in Southern Italy compared with Northern Italy. No differences in survival were observed by sex and by socioeconomic status. The Cox proportional hazard model was used to evaluate the effect of each variable adjusted for all the others present in the model. Presence of CHD (odds ratio = 3.27; 95% confidence interval (C.I.) 2.31-4.63), birth in the South (odds ratio = 2.69; 95% C.I. 1.91-3.79), and low birth weight (odds ratio = 1.87; 95% C.I. 1.29-2.72) were independently associated with survival. None of the other variables emerged as a statistically significant prognostic factor. Various hypotheses were considered to interpret the unexpected effect of place of birth on survival. Quality of medical care provided in the South of Italy is the most likely determinant of the high mortality observed among children with DS born in that area of Italy. Such differences in survival within the same country could occur in other developed nations as well.