Updated project metadata. The enamel proteome includes a range of proteins which are well-preserved in archaeological settings but have so far received less study than the sex-specific sequencing of enamel. We look beyond sex-specific sequencing of amelogenin to investigate the potential of several serum proteins, including immunoglobulin gamma (IgG), the major immunoglobulin found in blood serum, and C-reactive protein (CRP) which is associated with inflammatory response, to provide insight into the health and stresses experienced by individuals in the past. We apply this approach to enamel samples from Mission-Period ancestral Ohlone interred at Asistencia San Pedro y San Pablo (CA-SMA-71/H; n=11). For comparison, we also examine enamel from historic-period European-Americans interred in the City Cemetery in San Francisco, and extracted third molars from present-day military cadets. Results indicate that IgG is elevated among individuals at the asistencia relative to samples from present-day military cadets (n=8), or historic City Cemetery individuals (ANOVA with post-hoc Tukey Kramer tests, p < 0.02). Further, the inflammatory protein CRP, normally expressed at much lower levels than IgG, was present in 55% (6 of 11) of the asistencia samples, and in 17% (2 of 12) of the historic City Cemetery samples, but was not detected in enamel samples from contemporary military cadets. While more studies are needed, we argue that the difference in IgG could reflect higher levels of chronic diseases such as tuberculosis among Ohlone living within the Mission system, while the presence of measurable amounts of CRP could relate to high degrees of physical, social, and emotional stresses. To our knowledge, this is the first paleoproteomic study of immune proteins in tooth enamel. The ability to track immune responses during tooth formation could provide valuable and high-resolution information on ancient health and disease at the level of the individual over archaeological time-scales.