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Spatial variation in particulate matter–related health and toxicological outcomes is partly due to its composition. We studied spatial variability in particle composition and induced cellular responses in Mexico City to complement an ongoing epidemiologic study. We measured elements, endotoxins, and polycyclic aromatic hydrocarbons in two particle size fractions collected in five sites. We compared the in vitro proinflammatory response of J774A.1 and THP‐1 cells after exposure to particles, measuring subsequent TNFα and IL‐6 secretion. Particle composition varied by site and size. Particle constituents were subjected to principal component analysis, identifying three components: C₁ (Si, Sr, Mg, Ca, Al, Fe, Mn, endotoxin), C₂ (polycyclic aromatic hydrocarbons), and C₃ (Zn, S, Sb, Ni, Cu, Pb). Induced TNFα levels were higher and more heterogeneous than IL‐6 levels. Cytokines produced by both cell lines only …