Objective <p>To determine the proportion of children with acute lymphoblastic leukemia (ALL) with hypoglobulinemia during maintenance chemotherapy and to determine its association with severe febrile illnesses.</p> Methods <p>Children with ALL receiving maintenance chemotherapy were prospectively recruited and serum immunoglobulin levels (IgG, IgM, IgA) were measured by turbidimetric method. Children were followed up for severe febrile illnesses for 6&#xa0;months or till the completion of treatment.</p> Results <p>We enrolled 199 children with mean (SD) age 82.03 (39.34) months; 58, 52, 47, and 42 children had received 0–6, 7–12, 13–18 and 19–24 months of maintenance chemotherapy, respectively. Hypo-IgG, hypo-IgA, and hypo-IgM were seen in 56.8%, 80.4%, and 86.4% of children. 91 (45.7%) children developed 147 episodes of severe febrile illness. Older age (&gt; 5&#xa0;years) was associated with decreased risk [odds ratio 95% CI] of hypo-IgG [0.540 (0.297, 0.982), <i>P</i> = 0.044], hypo-IgA [0.030 (0.011, 0.088), <i>P</i> = 0.001], and hypo-IgM [0.323 (0.117, 0.894), <i>P</i> = 0.030] and female gender had decreased risk of hypo-IgG (0.539 (0.305, 0.953), <i>P</i> = 0.033). Older age decreased the risk [0.585 (0.328, 1.041), <i>P</i> = 0.014] and girls were at increased risk [(1.118, 3.488), <i>P</i> = 0.019] of severe febrile illness. Hypoglobulinemia did not increase the risk of severe febrile illness.</p> Conclusion <p>Hypoglobulinemia was not found to be an independent risk factor for severe febrile illnesses in children with ALL receiving maintenance chemotherapy.</p>