In 1959, cytologic studies demonstrated that Down syndrome was associated with a nondisjunction now known as trisomy 21. Twenty years earlier (1932-39), at least three writers conjectured, independently of one another, that Down syndrome might be a form of nondisjunction: Petrus J. Waardenburg (1932), Adrien Bleyer (1934), and G. Fanconi (1938). In separate papers, Raymond Turpin (1937), Walter E. Southwick (1939), and Lionel S. Penrose (1939) also proposed that Down syndrome could be a chromosomal anomaly, but without specifying nondisjuction. However, these conjectures were largely ignored by contemporary medical writers. This essay (1) explores the background and context of early conjectures that Down syndrome is a form of nondisjunction, (2) provides some possible reasons why these conjectures were not given greater credence, and (3) traces early efforts to assimilate Down syndrome and other genetic disorders to what Robert Koch called the etiologic standpoint.