Infections still remain a major cause of therapy-associated morbidity and death in patients with malignant diseases. To further lower the risk of serious and long-lasting infections by additional supportive measures, detailed information on the frequency and characteristic features of infections is needed. Therefore, patient data from 112 children with acute lymphoblastic leukemia and T-cell lymphoma who were treated according to the COALL-05-92 protocol in our department were analyzed for differences in the frequency and origin of febrile episodes in relation to age, immunological type of leukemia, treatment in group assessed as being at high or low risk of relapse, actual occurrence of relapse, and course of chemotherapy. At the time of diagnosis, low-risk patients more commonly presented with febrile episodes than high-risk patients. In total, patients developed a fever in 313 (24%) of 1,307 evaluated chemotherapy cycles. Febrile episodes were associated with microbiologically or clinically documented infections in 60% of all cases, while in 40% the fever was of unknown origin. Gram-positive pathogens had a markedly higher incidence than gram-negative or fungal ones. The incidence of febrile episodes during therapy appeared to be correlated with certain chemotherapeutic drug combinations. The highest rate was found after high-dose cytarabine and asparaginase causing a long period of leukopenia. However, after other chemotherapy courses with a similar duration of leukopenia the incidence of febrile episodes was significantly lower, suggesting that specific interactions of different chemotherapeutic agents with the immune response might be an important factor in development of infections. Individual factors might also account for an increased incidence of infections, since the number of high-risk patients with recurrent infections was significantly higher than expected on the basis of statistical evaluation. In conclusion, our findings suggest that the risk of infections during chemotherapy may not only be influenced by leukopenia, but that drug-specific effects of the various chemotherapeutic agents and individual factors may also be important contributory factors. These observations must be further expanded in prospective studies so that new tailored supportive care protocols can be elaborated.