Transthyretin (TTR) is a semi-abundant (0.1-0.2 mg/mL), tetrameric plasma protein that plays a role in transport of thyroxine and the retinol-binding protein complex. TTR is strongly implicated in amyloid diseases, which are caused by misfolding and aggregation of proteins. Transthyretin amyloidosis occurs in a hereditary (ATTRh) and wildtype (ATTRwt) form. Hereditary transthyretin amyloidosis is a progressive and fatal autosomal dominant disorder caused by > 120 reported TTR single nucleotide polymorphisms (SNPs). Amyloidogenic TTR SNPs destabilise circulating tetrameric TTR, thus promoting transthyretin amyloid (ATTR) formation, tissue deposition, and end-organ damage. Historically, the only treatment for ATTRh was liver transplantation, however, novel treatments including TTR-tetramer stabiliser and TTR-synthesis suppressor drugs have progressed recently into clinical practice. Current clinical guidelines recommend TTR genotyping for both ATTR patients as well as the asymptomatic relatives of variant TTR carriers to enable ATTRh treatment and to identify variant TTR carriers for regular clinical monitoring. However, due to relatively high cost and low throughput, TTR genotyping is currently expensive to fund for public health organisations and unsuitable for population-level screening. Mass spectrometry (MS)-based analyses, using techniques established in both top-down and bottom-up proteomics studies, have been proposed as an alternative to genetic testing. However, methods published to date have not demonstrated suitable coverage of potential TTR SNPs, while also being disadvantaged by low throughput and high cost. In response to the unmet clinical need for rapid, inexpensive identification of amyloidogenic TTR variants, we have developed companion LC-MS methods to analyse TTR at both the intact protein and enzymatically-digested peptide level. TTR is enriched from serum or plasma and prepared for LC-MS analysis using simple, inexpensive reagents. Intact and digested TTR are analysed by top-down data-dependent and bottom-up data-independent acquisition methods with a combined run-time of ~10 minutes. The resulting raw data are processed through separate software packages, the output of which is combined using a custom Python script accessed through a web-browser interface to determine patient TTR genotype. The performance of the LC-MS methods in detecting TTR SNPs was evaluated using plasma samples obtained from genotyped patients from the Westmead Amyloidosis Service, the quaternary amyloidosis service for NSW.