Automated cell counters are widely used in modern clinical laboratories to provide reliable, fast, and cost-effective complete blood counts (CBCs), white blood cell differentials, and reticulocyte measurements. In addition, some advanced instruments provide novel parameters, such as the hemoglobin content of reticulocytes or the percentage of hypochromic cells, and are capable of analysis of a variety of body fluids. Bayer recently introduced the ADVIA 2120 system as an automation-ready cell counter for mid- to high-volume testing in the clinical laboratory. This instrument, which builds on the established technology of the ADVIA 120 system, operates with a cyanide-free method for hemoglobin measurement, has a new user interface, and can routinely analyze biological fluid samples in addition to blood. We used 749 samples from 6 worldwide trial sites to evaluate the clinical performance of this new device. Accuracy of the ADVIA 2120 system versus its predecessor model, the ADVIA 120 system, was excellent for all CBC and white cell differential parameters and reticulocyte counts (all correlation coefficients except for basophils >0.9). Correlation of the white cell differential with the standard manual method and within-run precision of the ADVIA 2120 system also was very good. Use of the novel cyanide-free method for hemoglobin measurement had no clinically significant impact on hemoglobin results, even in patients with hemoglobinopathies. We concluded that the ADVIA 2120 system has clinically equivalent performance to the ADVIA 120 system.