Background: White blood cell (WBC) counts are used to monitor bone marrow function and to screen for infections. The HemoCue WBC DIFF Point-Of-Care (POC) instrument classifies WBCs through cell image recognition. To evaluate its suitability for monitoring cancer patients, we examined its performance in samples from patient with leukopenia and in samples containing nRBC. Methods: Sysmex samples with WBCs 0.05-3.40 × 10⁹/L were examined on the HemoCue WBC DIFF, and the correlations between the instruments were assessed by Deming regression for total WBC, neutrophils, and lymphocytes. The theoretical CV% (CVt), calculated from number of cells counted by the HemoCue WBC DIFF, was used to determine the statistical error of the WBC counts. The interference of nRBC was also evaluated. Results: The counting variation was primarily the source of statistical error in the lower counts with an imprecision between 3.8–9.2% for total WBC (0.56–2.29 ×10⁹/L), 8.7–14.3% for neutrophils (0.36–1.33 ×10⁹/L) and 9.8–15.1% for lymphocytes (0.35–0.89 ×10⁹/L). The correlation coefficient was between 0.658 and 0.986—poorest for lymphocytes. The total WBC count on the HemoCue WBC DIFF was significantly increased in nRBC samples due to lymphocyte count overestimation, and not by other WBCs. Conclusions: The HemoCue WBC DIFF provided reliable and accurate counts of total WBC, neutrophil, and lymphocyte in leukopenic samples. Until POC instruments that can perform an accurate complete blood count are available, the HemoCue WBC DIFF can be used to assist physicians in making decisions in situations of postchemotherapy leukopenia and neutropenia.