Background The i-STAT (iST) and GEM Premier ChemSTAT (ChmST) are point-of-care systems that measure electrolytes, metabolites, acid-base parameters, and hematocrit on blood. We compared results for creatinine, urea (blood urea nitrogen [BUN]), total carbon dioxide (tCo2), and ionized calcium (ion Ca) on blood by the ChmST and iST to Beckman DxC600 (DxC600) results for creatinine and urea on plasma and GEM Premier 5000 (GEM5K) results for ion Ca and tCo2 on blood. Methods 107 heparinized blood specimens were analyzed on the ChmST and iST systems, with plasma tested by DxC600 for creatinine and BUN and blood tested by GEM5K for ion Ca and tCo2. We evaluated the methods primarily by the mean and SD of the biases at clinically relevant concentrations. Results The correlations of ChmST and iST results on blood for creatinine, BUN, ion Ca, and tCo2 correlated to plasma by the DxC600 and to blood by the GEM5K were r ≥ 0.98 for all analytes except for ion Ca on the iST (r = 0.93). The mean and SD of biases were within clinically and analytically acceptable limits for all methods except for tCo2 on the ChmST, which measures bicarbonate with a bicarbonate-sensing electrode. Also, creatinine and BUN by the ChmST were less affected by icterus or hemolysis than were the DxC600 (icterus) and the iST (hemolysis). Conclusions The ChmST and iST results on blood demonstrated strong correlations with each other and with the DxC600 results on plasma. We conclude the ChmST provides reliable results for whole blood creatinine, urea, ion Ca, and tCo2.