Hereditary spherocytosis (HS) is a common red blood cell disorder. It has been shown that the mean sphered corpuscular volume (MSCV), an artificial volume, is always lower than the MCV in HS and also in some autoimmune haemolytic anaemia (AIHA). Our purpose was to assess the reliability of MSCV in routine practise, and its relevance in screening for HS. Comparison of MSCV and MCV was undertaken in a prospective study of 366 patients with anaemia. In addition, included were patients previously diagnosed to have HS (n = 33) or AIHA (n = 16). When MSCV was lower than MCV, a flow cytometric (FC) test for HS was performed. Delta (MCV-MSCV) values >9.6 fl were obtained for all HS patients. A wider spread of delta (MCV-MSCV) values was obtained for AIHA patients whose red cells gave FC test results negative for HS. In the ROC curve analysis, the determination of delta (MCV-MSCV) value has a 90.57% specificity and 100% sensitivity for HS. MSCV is a reliable automated parameter indicating possible HS. When a delta (MCV-MSCV) value is >9.6 fl, the FC test and the Coombs test are required in the differential diagnosis of HS and some AIHA.