BACKGROUND: The National Children's Study is the most ambitious study ever attempted in the United States to assess how environmental factors impact child health and development. It aims to follow 100,000 children from gestation until 21 years of age. Success requires breaking new interdisciplinary ground, starting with how to select the sample of > 1,000 children in each of 105 study sites; no standardized protocol exists for stratification of the target population by factoring in the diverse environments it inhabits. Worcester County, Massachusetts, like other sites, stratifies according to local conditions and local knowledge, subject to probability sampling rules. OBJECTIVES: We answer the following questions: How do we divide Worcester County into viable strata that represent its health-relevant environmental and sociodemographic heterogeneity, subject to sampling rules? What potential does our approach have to inform stratification at other sites? RESULTS: We developed a multivariable, vulnerability-based method for spatial sampling consisting of two descriptive indices: a hazards/stressors exposure index (comprising three proxy variables), and an adaptive capacity/sociodemographic character index (five variables). Multivariable, health-relevant stratification at the start of the study may improve detection power for environment-child health associations down the line. Eighteen strata capture countywide heterogeneity in the indices and have optimal relative homogeneity within each. They achieve comparable expected birth counts and conform to local concepts of space. CONCLUSION: The approach offers moderate to high potential to inform other sites, limited by intersite differences in data availability, geodemographics, and technical capacity. Energetic community engagement from the start promotes local stratification coherence, plus vital researcher-community trust and co-ownership for sustainability.