The author analyzed quantitative data from an NIMH-funded longitudinal study of 322 women with persistent severe mental illness (SMI) and qualitative data from semistructured interviews with 82 of the women who ever lost custody of a child. The purpose was to test the hypothesis, derived from human ecology theory, that individual and environmental factors combine with mental illness to predict a history of child custody loss. The final model supported the increased likelihood of child custody loss for most women with persistent mental illness. Results provide support for directing policy advocacy and services toward ensuring a network of formal and informal support and resources and strengthening parenting skills and values for mothers with persistent SMI.