Abstract Background: Assuring/demonstrating metrologic traceability of in vitro diagnostics necessitates the availability of measurand-specific reference measurement systems (RMSs) and the possibility for industry to work with competent reference measurement laboratories (RMLs). Here we report the results of a European project to investigate the feasibility of developing a RMS for serum total thyroxine. Methods: Four candidate RMLs (cRMLs) developed/implemented variants of a candidate reference measurement procedure (cRMP) based on isotope dilution–liquid chromatography–mass spectrometry. The sole constraint implemented was calibration with a common thyroxine primary calibrator. The RMPs were externally validated and assessed for comparability in round-robin trials using common samples, i.e., 5 lyophilized and 33 frozen native sera. At the same time, the performance of the cRMLs organized in a network was assessed. For uniform external quality assessment, common performance specifications were agreed on. Results: All cRMLs performed the cRMPs with fulfillment of the predefined specifications: total and between-laboratory CVs ≤2.0% and 2.5%, respectively, and a systematic deviation ≤0.9%, estimated with a target assigned from the mean of means obtained by the cRMLs. The mean expanded uncertainty for value assignment to the native sera was 2.1%. Conclusions: A network of cRMLs, with externally conformed competence to properly perform RMPs, has been established. Performance specifications were defined and will form the basis for admittance of new network members. A serum panel, successfully targeted during the validation process, is available for split-sample measurements with commercial routine measurement procedures. The model can now be used for other measurands for which traceability to the Système International d’Unités is needed.