Acute lymphoblastic leukemia (ALL) of infancy has in contrast to all other age groups a less favorable prognosis. In order to determine the possible causes and biological principles for impaired outcome of infant patients in five consecutive clinical trials ALL-BFM 1970-1986, both clinical characteristics and biological features for one hundred and ninety-six patients aged two years and less have been evaluated retrospectively (forty-two infants under one year of age). The observations illustrate, that less favorable subtypes of childhood ALL are more frequent in these children, preferably in infants aged six months and less, explaining decisively the impaired prognosis. These subtypes are characterized by large tumor burden (p = less than 0.001), initial central nervous system (CNS) involvement (p = less than 0.001), and a high CNS relapse rate (p = 0.03). Phenotypically the undifferentiated leukemic blast cells show negative reactions for cALLa and often for Tdt (0-ALL and AUL; p = less than 0.001). The switch to prognostically more favorable ALL subtypes occurs about the end of the first year of life. Nevertheless, early failures by non-response or late-response seem not to influence the poorer outcome. However, compared to the preceding trials, results of studies ALL-BFM 81 and ALL-BFM 83 were significantly improved in respect to the probability of continuous complete remission for infant patients (pCCR less than 1 y: 0.44 vs. 0.28), confirming that treatment by itself is one of the major prognostic determinants.