Background: Currently, two systems for continuous tissue glucose monitoring (CGM) (Dexcom® G5 [DG5] and FreeStyle Libre [FL]) are intended to replace blood glucose monitoring (BGM) and, according to manufacturer labeling, are distributed as such in some jurisdictions, including the United States and the European Union.Methods: The measurement performance of these two systems in comparison with a BGM system was analyzed in a 14-day study with 20 participants comprising study site visits, which included phases of induced rapid glucose changes, and home use phases. Performance analysis was mainly based on deviations between CGM readings and BGM results. Sensor-to-sensor precision was also analyzed.Results: Approximately 25% of DG5 and FL results showed differences from BGM results exceeding 15 mg/dL or 15% (at glucose concentration below or above 100 mg/dL, respectively) at times of therapeutic decisions, and ∼5% of differences exceeded 30 mg/dL or 30%. Performance was different depending on the setting (study site visits, home use phases, and phases of induced rapid glucose changes). In consensus error grid (CEG) analysis, both systems showed >99.5% of results within the clinically acceptable zones A and B.Conclusions: In this study, both systems showed deviations from blood glucose (BG) measurements, the current standard approach in diabetes therapy. Although a large percentage of results was found in CEG zones A and B, for approximately one in four therapeutic decisions, CGM and BG readings differed by at least 15 mg/dL or 15%. Such deviations should be taken into account when using CGM systems.