Variation in karyotypes and RAPD patterns of genetically related strains of Cryptococcus neoformans were analyzed. Capsular and filamentous mutants usually differ in their karyotypes from wild-types, but the RAPD patterns were found to be similar. Karyotype differences were observed in most heterothallic matings, but RAPD patterns remained identical. After self-sporulation of a diploid strain, minor chromosomal length polymorphism and minor changes in the RAPD types occurred. Three mechanisms, either alone or in combination, may in varying degrees contribute to the karyotype variation of C. neoformans: (1) mitotically induced changes; (2) karyotype changes as a result of meiotic recombination, and (3) mutagen-induced changes. The present data do not support the meiotic maintenance hypothesis, which claims that the amount of CLP generated is inversely proportional to the frequency of meiosis.