The relationship between advanced maternal age and increased risk of trisomic offspring is well known clinically but not clearly understood at the level of the oocyte. A total of 383 oocytes that failed fertilization from 107 patients undergoing in vitro fertilization were analyzed by FISH using X-, 18-, and 13/21-chromosome probes simultaneously. The corresponding polar bodies were also analyzed in 188 of these oocytes. The chromosomes in the oocyte and first polar body complement each other and provide an internal control to differentiate between aneuploidy and technical errors. Two mechanisms of nondisjunction were determined. First, nondisjunction of bivalent chromosomes resulting in two univalents going to the same pole and, second, nondisjunction by premature chromatid separation (predivision) of univalent chromosomes producing either a balanced (2 + 2) or unbalanced (3 + 1) distribution of chromatids into the first polar body and M-II oocytes. Balanced predivision of chromatids, previously proposed as a major mechanism of aneuploidy, was found to increase significantly with time in culture (P < .005), which suggests that this phenomenon should be interpreted carefully. Unbalanced predivision and classical nondisjunction were unaffected by oocyte aging. In comparing oocytes from women <35 years of age with oocytes from women > or = 40 years of age, a significant increase (P < .001) in nondisjunction of full dyads was found in the oocytes with analyzable polar bodies and no FISH errors. Premature predivision of chromatids was also found to cause nondisjunction, but it did not increase with maternal age.