Per- and polyfluoroalkyl substances (PFAS) are a class of manmade chemicals linked to concerning health outcomes such as infertility, various cancers, and increased cholesterol. Due to these health concerns, several legacy PFAS such as perfluo-rooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) have been voluntarily phased out of the United States since the early 2000s. However, to continue providing consumer products with PFAS-specific characteristics such as water, grease and heat resistance, emerging PFAS were introduced over the last 25 years to replace the legacy chemicals of concern. The presence and accumulation of these emerging PFAS, however, remains largely unexplored due to the complexity of their identification and analysis. Here, we analyzed a unique sample set of serum samples from 52 groups containing three people (n=156). Each group consisted of one person with an autoimmune disease and two sex, age and demographically matched controls, where one was a healthy sibling and the other was unrelated. These samples were collected from 2003 to 2021 and evaluated using both a targeted and non-targeted analysis workflow. These analyses provide an assessment of how PFAS exposure has changed since 2003, explore linkages between PFAS and autoimmune diseases, and emphasize the need for more PFAS studies on chlorinated PFAS and polyfluoroalkyl phosphates (DiPAPs) and perfluoroalkyl phosphinic acids (PFPis) classes due to their detections in human blood.