BACKGROUND: Lipoprotein(a) [Lp(a)] is an independent risk factor for cardiovascular diseases (CVD). Recent clinical guidelines recommend measuring Lp(a); however, the lack of Lp(a) assay standardization presents challenges to using common clinical decision points. Assay standardization may minimize inter-assay variability. This improves consistency in CVD risk assessment and evaluations of Lp(a) therapeutic efficacy. Genetically determined size variations in the defining apolipoprotein(a) [apo(a)] protein contribute to inter-individual Lp(a) heterogeneity. Individuals who express 2 apo(a) isoforms have 2 sizes of apo(a) in circulation, further contributing to Lp(a) heterogeneity. OBJECTIVE: The Centers for Disease Control and Prevention's Clinical Standardization Programs (CDC CSP) recently launched an Lp(a) standardization program based on the International Federation of Clinical Chemistry endorsed liquid-chromatography mass spectrometry-based reference measurement procedure (RMP). As part of this program, CDC CSP conducted an interlaboratory comparison study to evaluate current Lp(a) inter-assay variability and to investigate potential factors contributing to measurement variability. METHODS: Eight clinical laboratories measured Lp(a) in 40 individual donor serum samples and 3 serum pools. Serum samples were immunophenotyped by Western blot analysis to determine Lp(a) isoform sizes. Sample concentrations were measured in duplicate over 2 independent runs. RESULTS: Assay-specific Lp(a) measurements demonstrated good linear correlation with the RMP. Lp(a) inter-assay measurement variations ranged from 3.3% to 69.1% across individual samples; however, Lp(a) inter-assay coefficients of variation did not increase in a concentration-dependent manner and were not correlated with Lp(a) isoform sizes. CONCLUSION: This study provides new insights into Lp(a) inter-assay variability and assay performance in clinical laboratories that will guide future standardization efforts.