Introduction: Guillain-Barre Syndrome (GBS) is an immunologically mediated acquired polyradiculoneuropathy. The incidence of GBS is 1–2 cases per 100,000 in children. Only a few cases of GBS associated with Acute Lymphoblastic Leukemia (ALL) were reported in the literature and none, to our knowledge, in association with Type-1 Diabetes Mellitus (T1DM). We are reporting GBS in two children diagnosed as ALL and T1DM. Cases description:  Child A is a 14 years-old male on maintenance therapy for B-ALL with Central Nervous System (CNS) relapse.  Child B is a 12 years-old boy diagnosed as T1DM 2.5 years earlier, with good glycemic control. Both children developed acute progressive symmetrical weakness of both lower limbs, associated with right-sided facial palsy in child A and preceded by 4 months of numbness for child B. Both children were misdiagnosed as peripheral neuropathy which is either drug-induced (child A) or vitamin B12 deficiency (child B). In both children, electrophysiological studies showed proximal demyelination affecting the lower limbs and treatment was initiated with Intravenous immunoglobulin (0.4 g/kg for 5 days) with an excellent response. The cerebrospinal fluid (CSF) analysis of child A showed 95% blast cells, a second CNS relapse was diagnosed and re-induction chemotherapy was started. Conclusion: Although rare, GBS may overlap with other systemic disease and even mask the underlying diagnosis. CSF and electrophysiological studies are mandatory for any case of GBS, not only to increase the accuracy of the diagnosis but also to exclude other diagnoses; CNS relapse or peripheral neuropathy in our cases.