We set out to determine if the clinical course or genetic profiles of patients with cystic fibrosis who had meconlum ileus differed from those of other patients with cystic fibrosis. Since 1950 we have followed 158 patients with meconlum ileus among 1175 patients with cystic fibrosis (13.4%). Patients with meconium ileus had lower birth weight (3026±610 gm) than patients with no meconium ileus (3169±534 gm; p<0.008); the deficit was especially evident in female patients. Survival in the first year of life increased from 55% in those born between 1958 and 1972 to 96% in those born between 1973 and 1987. Since 1973 the median survival of male and female patients with meconium ileus was similar to that in female patients with no meconium ileus (21 years), whereas 78% of males with no meconium ileus survived to this age (p<0.0001). Patients with meconium ileus born before 1972 had lower weight and height percentiles at age 13 years compared with patients with no meconium ileus, but this difference was not as apparent in patients born after 1973. There were no differences between the two groups in forced vital capacity, forced expiratory volume in 1 second, or forced expiratory flow in the middle half of forced vital capacity. Patients with meconium ileus acquired Pseudomonas aeruginosa at a younger age than did patients with no meconium ileus (4.20±4.67 vs 7.18±5.19 years), but there was no difference in age of acquisition of P. cepacia. In families in which the first child had meconium ileus, 29% of subsequent siblings with cystic fibrosis had meconium ileus, compared with 6% of siblings born to familles in which the first child did not have meconium ileus. Allelic frequencles and haplotypic variants for cystic fibrosis chromosomes with respect to DNA markers closely linked to the cystic fibrosis locus were similar in families with cystic fibrosis with meconium ileus and those with no meconium ileus. These findings suggest that patients with cystic fibrosis and those without meconlum ileus do not have major intrinsic differences and that the previously poor outlook in patients with meconium ileus has improved greatly.