Erythrocytes resistant to standard lysing reagents are known to occur in sickle cell disease. These lyse-resistant erythrocytes can cause aberrant automated leucocyte counts and differentials. The ability of the Cell-Dyn 3500 automated haematology analyser to eliminate resistant erythrocytes and accurately count and differentiate leucocytes was evaluated. Samples were obtained from paediatric patients with sickle cell disease or haemoglobin SC disease. The Cell-Dyn 3500, using impedance and optical counting with a hypotonic salt "extended lyse mode', was compared to the Cell-Dyn 3000, an optical analyser that also uses a hypotonic salt lyse, the Cell-Dyn 400, a "hard detergent lyse' impedance counter, and a reference 400-cell manual white cell differential (National committee for Clinical Laboratory Standards [NCCLS] Approved Guideline H20-A). Seventy-five samples from patients with sickle cell disease or haemoglobin SC disease were evaluated for total leucocyte count, percentage of lymphocytes, percentage of neutrophils, and nucleated red blood cells (NRBC) flags. The Cell-Dyn 3500 correlated well with Cell-Dyn 400 leucocyte counts, with a correlation coefficient of 0.95. When compared to the manual differential, the correlation coefficient for lymphocytes was 0.93 and for neutrophils 0.95. The Cell-Dyn 3500 NRBC flag had a sensitivity of 47.7% and a specificity of 80.6%. The predictive value of a positive flag was 77.7%. The Cell-Dyn 3500's extended lyse mode clearly enhances the accuracy of leucocyte counts and differentials in patients with sickle cell disease.