ETV6::RUNX1 is the most common fusion gene in childhood acute lymphoblastic leukaemia (ALL) and is associated with favorable outcomes, especially in low‐risk children. However, as many as 10% of children relapse within 3 years, and such early relapses have poor survival. Identifying children at risk for early relapse is an important challenge. We interrogated data from 87 children with low‐risk ETV6::RUNX1‐positive B‐cell ALL and with available preserved bone marrow samples (discovery cohort). We profiled somatic point mutations in a panel of 559 genes and genome‐wide transcriptome and single‐nucleotide variants. We found high TIMD4 expression (> 85th‐percentile value) at diagnosis was the most important independent prognostic factor of early relapse (hazard ratio HR = 5.07 1.76, 14.62; p = 0.03). In an independent validation cohort of low‐risk ETV6::RUNX1‐positive B‐cell ALL (N = 68) high TIMD4 expression at diagnosis had an HR = 4.78 1.07, 21.36 (p = 0.04) for early relapse. In another validation cohort including 78 children with low‐risk ETV6::RUNX1‐negative B‐cell ALL, high TIMD4 expression at diagnosis had an HR = 3.93 1.31, 11.79 (p = 0.01). Our results suggest high TIMD4 expression at diagnosis in low‐risk B‐cell ALL in children might be associated with high risk for early relapse.