We conducted a case-control study in families of Down syndrome children with classical trisomy 21 (n = 188) and in a control group of families of children referred to the same hospital for benign diseases (n = 185). The low sibling number does not allow any conclusion about the risk for sibs but our results do not support an increased incidence of Down syndrome among second and third degree relatives of trisomy 21 children. The choice of the control group and the restriction to close relatives protect us against biases which may have interfered in previous studies reporting recurrence in families.