A matched case-control study of 100 mothers of Down syndrome children, 100 mothers of children with other defects (defect controls), and 100 mothers of children with no defects (normal controls) was carried out. All infants were born in upstate New York in 1980 and 1981. Matching was very close on maternal age for the normal controls but not for the defect controls. The risk ratios for the association of cigarette smoking around the time of conception with Down syndrome was 0.58 (90% confidence interval of 0.34-0.98) in the case-defect control comparison and 0.56 (90% confidence interval of 0.33-0.95) in the case-normal control comparison. Stratification by alcohol ingestion and maternal age did not abolish the negative trend to association. The results are contrary to that of an earlier study of others that found a positive association of older age and trisomy in spontaneous abortions. In fact, among mothers of Down syndrome cases over age 30 in this analysis, the risk ratio was lower than for younger mothers. (For case-normal control comparisons, the value was 0.39 [90% confidence interval of 0.17-0.87]). If not due to chance or confounding, the negative association in our data may be attributable to, among other factors, a selective effect of smoking upon survival or fertilizability of +21 gametes prior to conception or upon survival of +21 conceptuses after fertilization.