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Abstract ObjectivesThe immune system of milk (ISOM) creates a mother–infant immune axis that plays an important role in protecting infants against infectious disease (ID). Tradeoffs in the immune system suggest the potential for both protection and harm, so we conceive of two dimensions via which the ISOM impacts infants: promotion of protective activity and control of activity directed at benign targets. High variability in ISOM activity across mother–infant dyads suggests investment the ISOM may have evolved to be sensitive to maternal and/or infant characteristics. We assessed predictors of appropriate and misdirected proinflammatory ISOM activity in an environment of high ID risk, testing predictions drawn from life history theory and other evolutionary perspectives. MethodsWe characterized milk in vitro interleukin‐6 (IL‐6) responses toSalmonella enterica(a target of protective immune activity;N = 96) andEscherichia coli(a benign target;N = 85) among mother–infant dyads in rural Kilimanjaro, Tanzania. We used ordered logistic regression and mixture models to evaluate maternal and infant characteristics as predictors of IL‐6 responses. ResultsIn all models, IL‐6 responses toS.entericaincreased with maternal age and decreased with gravidity. In mixture models, IL‐6 responses toE.colideclined with maternal age and increased with gravidity. No other considered variables were consistently associated with IL‐6 responses. ConclusionsThe ISOM's capacities for appropriate proinflammatory activity and control of misdirected proinflammatory activity increases with maternal age and decreases with gravidity. These findings are consistent with the hypothesis that the mother–infant immune axis has evolved to respond to maternal life history characteristics.