Novel agents are needed for patients with refractory and relapsed acute lymphoblastic leukaemia (ALL). Combotox is a 1:1 mixture of two immunotoxins (ITs), prepared by coupling deglycosylated ricin A chain (dgRTA) to monoclonal antibodies directed against CD22 (RFB4‐dgRTA) and CD19 (HD37‐dgRTA). Pre‐clinical data demonstrated that Combotox was effective in killing both pre‐B‐ALL cell lines and cells from patients with pre‐B ALL. A clinical study of paediatric patients in which 3 of 17 patients with ALL experienced complete remission, supported the preclinical work and motivated this study. This study was a Phase I, dose‐escalation trial using Combotox in adults with refractory or relapsed B‐lineage‐ALL. A cycle consisted of three doses, with one dose given every other day. Dose levels were 3, 5, 6, 7 and 8 mg/m² per dose. Seventeen patients, aged 19–72 years, were enrolled in this multi‐institution study. The maximum tolerated dose was 7 mg/m²/dose (21 mg/m²/cycle) and vascular leak syndrome was the dose‐limiting toxicity. Two patients developed reversible grade 3 elevations in liver function tests. One patient achieved partial remission and proceeded to allogeneic stem cell transplantation. All patients with peripheral blasts experienced decreased blast counts following the administration of Combotox. Thus, Combotox can be safely administered to adults with refractory leukaemia.