Abstract Background The American Diabetes Association recommends that people with diabetes use self-monitoring to control their blood glucose concentration. To assess the need for standardization, we evaluated the variability among 5 of the most common monitors: MediSense® Precision Xtra™, Ascencia™ Dex®, Prestige Smart System™, OneTouch® Ultra®, and Accu-Chek® Advantage®. Methods We took steps to minimize preanalytical variation. We also eliminated user variability by using one trained operator to collect samples and perform all testing. Each monitor was used twice with each participant; one test was performed using an aged strip and the other using a fresh strip. We compared monitors using a separate ANOVA for each concentration range and strip lot. Results The total CVs and the within-strip lot CVs were not statistically different among monitors, ranging from 3.1% to 11.3% and from 2.1% to 8.5%, respectively. There were statistically significant differences among monitors for among-strip lot CVs, which ranged from nearly 0% to 7.5%. The degree of significance increased as the concentration range increased [3.9–5.5 mmol/l: p < 0.05; 5.6–7.7 mmol/l: p = 0.003; 7.8–11.1 mmol/l: p < 0.001]. The average percent difference between monitor pairs was statistically significant ( p < 0.05) in more than half of the paired comparisons, with significant differences ranging from 5.7% to 32.0%. Conclusions Monitor results can vary significantly so that agreement among them is poor. Standardization is necessary to minimize variability and to improve patient care.