Background An automated multiplex platform using capillary blood can promote greater throughput and more comprehensive studies in celiac disease (CD). Diagnostic accuracy should be improved using likelihood ratios for the post-test probability of ruling-in disease. Methods The Ig_plex™ Celiac Disease Panel on the sqidlite™ automated platform measured IgA and IgG antibodies to tTG and DGP in n = 224 CD serum or plasma samples. Diagnostic accuracy metrics were applied to the combined multiplex test results for several CD populations and compared to conventional single antibody ELISA tests. Results With multiple positive antibody results, the post-test probability for ruling-in untreated and treated CD increased to over 90%. The number of samples positive for more than one antibody also increased in untreated CD to ≥90%. Measurement of all four CD antibodies generate cut-off dependent accuracy profiles that can monitor response to treatment with the gluten-free diet (GFD). Higher positive tTG and DGP antibodies are seen more frequently in confirmed CD without (81%–94%) than with GFD treatment (44%–64%). In CD lacking biopsy confirmation, overall agreement of plasma to serum was ≥98% for all antibodies, and 100% for venous to capillary plasma. Conclusions The Ig_plex Celiac Disease Panel increases the likelihood of confirming CD based on the post-test probability of disease results for multi-reactive markers. Specific positivity profiles and cut-off intervals can be used to monitor GFD treatment and likely disease progression. Using serum, venous and capillary plasma yield comparable and accurate results.