A side by side comparison of the Cell Dyn 3000 SL and Coulter STKS using identical samples was performed over a four month period in the Clinical Hematology Laboratory at the University of Cincinnati Medical Center. A total of 444 samples comprised of 114 sophomore medical students and 330 randomly selected clinical patients were compared in 20 hemogram parameters, and the ability of each instrument to generate differential suspect flags was analyzed. Correlation coefficients for leukocytes, erythrocytes, hemoglobin, hematocrit, and platelets were 0.99. Correlation coefficients for the Cell Dyn and STKS compared with a 600 cell manual differential were 0.98 and 0.89 for neutrophils, 0.96 and 0.87 for lymphocytes, and 0.72 and 0.48 for monocytes, respectively. Both instruments demonstrated high precision and accuracy by internal and external quality control standards. Each analyzer exhibited strength as a screening instrument for abnormal cell populations. The Coulter STKS had overall sensitivity of 75%, specificity of 94%, 25% false negatives, and 6% false positives. Sensitivity, specificity, false negative and positive rates for the Cell Dyn 3000 SL were 68%, 92%, 32%, and 8%, respectively. Based upon this extensive side by side comparison using an identical sample population, it has been concluded that although statistically significant systematic bias (p < 0.05) exists between the two instruments, both analyzers can adequately support the needs of the clinical hematology laboratory.