Purpose <p>Transient neutropenia in early childhood is a relatively common condition often associated with neutrophil-specific autoantibodies; however, its connection to broader humoral immune system abnormalities remains poorly understood.</p> Methods <p>The current study investigated this relationship through a retrospective cohort analysis at a pediatric tertiary center in Switzerland.</p> Results <p>In total, 92 children aged 0 to 6 years seen at our hospital between January 2014 and December 2023 were included in the final cohort. Of the 68 children who underwent detailed immunological testing, 52 (77%) exhibited humoral abnormalities, with 24 (35%) classified as moderate and 28 (41%) as mild. Patients with humoral abnormalities exhibited neutrophil-specific autoantibodies less commonly (56% vs. 100%, <i>p</i> = 0.003), had higher minimum absolute neutrophil counts (ANC) (median minimum ANC 0.26 vs. 0.05 × 10⁹/L, <i>p</i> = 0.002), and a shorter duration of neutropenia (median duration 12.1 vs. 28.5 months, <i>p</i> = 0.001) compared to patients without abnormalities. Additionally, 36% of patients with humoral abnormalities had inadequate vaccine antibodies, compared to none in the group without abnormalities. These findings suggest that patients with humoral abnormalities may have a higher risk of infection and could benefit from additional counseling and timely booster vaccinations.</p> Conclusion <p>This study highlights a potential causal relationship between humoral immune system abnormalities and transient neutropenia in early childhood. Routine immunological assessments in children with early-onset (autoimmune) neutropenia are likely to aid in patient management and family counseling.</p>