The suppression of lymphopoiesis and immune competence during the maintenance phase in children with acute lymphoblastic leukemia (ALL) and the occurrence of infectious complications remain an unexplored area. In this study we assessed lymphocyte subpopulation disturbances during maintenance for childhood ALL along with the incidence, type, and severity of infections that occur during that period in the absence of neutropenia. Twenty-eight children (13 boys, 15 girls) with ALL aged 3-14 years (median 7 years) and treated according to the ALL-BFM 90/95 protocol were studied during maintenance for ALL. Complete white blood cell (WBC) counts and peripheral blood lymphocyte (PBL) analyses were performed. Major lymphocyte subsets (CD19+, CD3+CD4+, CD3+CD8+, CD3-CD16+CD56+, CD45RA+, CD45RO+) and markers of T-cell activation (CD25, CD38, CD69, HLA-DR) were analyzed with flow cytometry. Serum immunoglobulin G (IgG), IgA, and IgM levels were measured by a nephelometric assay. All infectious episodes during the study period were recorded in detail. Additionally, 41 age-matched immunocompetent children were used as controls. Absolute WBC counts (median, 3627/µL) and PBL counts (median, 1206/µL) were significantly below the age-adjusted control values (7400/µL and 2673/µL, respectively; P < 0001). B-lymphocyte, total CD4+, and memory CD4+ (CD4+CD45RO+) subsets were also significantly decreased (33/µL versus 377/µL [P <.0001], 531/µL versus 1045/µL [P <.01], and 80/µL versus 299/µL [P <.001], respectively). Significantly lower immunoglobulin levels were found in all patients. Twenty-two of the 28 patients presented with 74 episodes of a variety of minor infections (mostly respiratory viral , skin , and gastrointestinal ), none demanding prolonged hospital treatment. Our findings demonstrate a profound immunosuppression throughout maintenance therapy in children with ALL that has no major clinical impact in terms of increased incidence or severity of systemic infections.