BACKGROUND: Saline replacement is a difficult and time-consuming procedure employed to measure hemoglobin (Hb) levels when lipaemia interferes with the accurate determination of Hb content. As an alternative method, we tested the reliability of cellular Hb (cHb) measurement. METHODS: Forty-eight lipemic blood samples were analysed with the LH780 (or DxH 800; Beckman Coulter Inc., USA) and ADVIA 2120i (Siemens Healthcare Diagnostics, USA) instruments. We compared the Hb measurements obtained following saline replacement (srHb) with the cHb measurement and with the value of one-third of the hematocrit (1/3Hct). RESULTS: The bias estimate outcomes of cHb with srHb were found to be acceptable at all medical decision points. The average difference between the value of 1/3Hct and initial Hb, srHb, and cHb were 19.7%±3.3%, 2.3%±1.6%, and -0.1%±1.1%, respectively. CONCLUSIONS: cHb measurements may be a feasible alternative to srHb, when lipemia interferes with accurate Hb determinations.