Twenty-eight cases of Down syndrome with maternal serum alpha-fetoprotein (AFP) measured at second trimester were added to 137 previously reported cases. Seventy-eight percent of affected pregnancies had levels at or below the median AFP value, compared with 50% of unaffected pregnancies. Maternal age at delivery and serum AFP levels by multiples of the median were used to construct a table to determine the risk of Down syndrome. This was compared with the risk for a 35-year-old woman (one in 365). Similar risks were estimated for a 21-year-old with AFP below 0.4 multiples of the median, a 23-year-old below 0.5, a 26-year-old below 0.6, and a 29-year-old below 0.7 multiples of the median. This study provides guidelines for counseling pregnant women who have low serum AFP levels.