BACKGROUND: Alternative means of blood sampling continue to grow due to the scarcity of phlebotomists and the need for person-centered care. It is crucial to consistently support these alternative blood sampling innovations with scientific evidence to guarantee the quality of care, especially when implementing for instance Lateral Upper-arm Blood Collection (LUBC) for use at home. Knowledge gaps remain in how to quantify imprecision introduced by the collection method and its impact on clinical use. METHODS: We developed the Six Sigma analysis for alternative Sampling methods, including sampling method-induced imprecision, accuracy and precision, called σ RESULTS: The biggest source of imprecision for all analytes was sampling method-induced imprecision, which, for the first time, was quantified, resulting in a varying effect on the clinical usability. TAP® II showed acceptable analytical performance for ALP, bilirubin, HDL-cholesterol, CRP and sodium. Unacceptable analytical performance was found for ALT, AST, cholesterol, creatinine, GGT, HbA1c, potassium, LDH and triglycerides. CONCLUSION: Alternative blood sampling innovations hold promise for advancing diagnostic care, aiming to deliver accessible decentralised sample collection at home that does not require phlebotomist involvement. However, sampling method-induced imprecision should not be overlooked in the performance assessment to guarantee responsible development that will contribute to the success and desirable societal impact of alternative sampling technologies.