Serological responses reveal recent and historical exposure to pathogens, as well as the state of autoimmune and other chronic conditions, including cancer. Serological tests either assess one or a few antigens in many people, or multiple antigens for modest sample sizes. Here, we describe a multiplexed serology method that evaluates samples at the scale of thousands1. This molecular epidemiology tool operates at a population scale sufficient to evaluate broadly how various infectious exposures or autoimmune responses affect health. The method employs full-length folded proteins, is quantitative over a wide dynamic range and performs favorably compared with commercial clinical assays. Responses to 39 bacteria species/strains and 99 viruses in 2400 people were evaluated. Subjects with longitudinal data showed quantitative stability of response to all antigens over the six-month time window, enabling the detection of intervening clinical events. Variation over this time period was low enough to be compatible with clinical use. These data revealed intervening infections, vaccinations, and age and gender-related prevalence data for EBV, HPV and Rubella. The Multiplexed In-Solution Protein Array (MISPA) platform employs a solution-based protein library, each protein antigen covalently linked to a unique DNA barcode. The use of barcodes, in lieu of attaching proteins to a surface, allowed antibody and target antigen to interact with solution phase kinetics, and provided a quantitative dynamic range over several orders of magnitude. The platform is highly scalable; a recent study included testing 11,000 samples for responses to 180 different targets, yielding more than 2 million data points. We expect this highly adaptable method will find broad application in immune profile tracking.