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Summary: Anti‐Ro60 is one of the most common and clinically important serum autoantibodies that has a number of diagnostic and predictive capabilities. Most diagnostic laboratories report this simply as a qualitative positive/negative result. The objective of this study was to examine the clinical and serological relevance of a novel subset of anti‐Ro60 in patients who display low levels of anti‐Ro60 (anti‐Ro60low). We retrospectively identified anti‐Ro60 sera during a 12‐month period at a major immunopathology diagnostic laboratory in Australia. These all were anti‐Ro60‐precipitin‐positive on the diagnostic gold standard counter‐immuno‐electrophoresis (CIEP). Lineblot immunoassay was used to stratify patients into either anti‐Ro60low or anti‐Ro60high subsets. We compared the medical and laboratory parameters associated with each group. Enzyme‐linked immunosorbent assay (ELISA) and mass spectrometry techniques were used to analyse the serological and molecular basis behind the two subsets. Anti‐Ro60low patients displayed less serological activity than anti‐Ro60high patients with less intermolecular spreading, hypergammaglobulinaemia and less tendency to undergo anti‐Ro60 isotype‐switching than anti‐Ro60high patients. Mass spectrometric typing of the anti‐Ro60low subset showed restricted variable heavy chain subfamily usage and amino acid point mutations. This subset also displayed clinical relevance, being present in a number of patients with systemic autoimmune rheumatic diseases (SARD). We identify a novel anti‐Ro60low patient subset that is distinct from anti‐Ro60high patients serologically and molecularly. It is not clear whether they arise from common or separate origins; however, they probably have different developmental pathways to account for the stark difference in immunological maturity. We hence demonstrate significance to anti‐Ro60low and justify accurate detection in the diagnostic laboratory. [ABSTRACT FROM AUTHOR]