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Although human twin studies have revealed the combined contribution of heritable and environmental factors in shaping immune system variability in blood, the contribution of these factors to immune system variability in tissues remains unexplored. The human uterus undergoes constant regeneration and is exposed to distinct environmental factors. To assess uterine immune system variation, we performed a system-level analysis of endometrial and peripheral blood immune cells in monozygotic twins. Although most immune cell phenotypes in peripheral blood showed high genetic heritability, more variation was found in endometrial immune cells, indicating a stronger influence by environmental factors. Cytomegalovirus infection was identified to influence peripheral blood immune cell variability but had limited effect on endometrial immune cells. Instead, hormonal contraception shaped the local endometrial milieu and immune cell composition with minor influence on the systemic immune system. These results highlight that the magnitude of human immune system variation and factors influencing it can be tissue specific. Editor's summary: Baseline differences in the immune system between individuals are driven by both heritable and nonheritable, environmental factors. By analyzing endometrial and peripheral blood immune cells collected from monozygotic twins, Bister et al. measured the tissue-specific contributions of nonheritable effects on immune system variation. Although peripheral blood immune cells were largely shaped by genetics, environmental factors including hormonal contraception contributed more strongly to the variation in endometrial immune cells and soluble proteome. Together, these findings demonstrate that the human immune system can be highly variable and driven by nonheritable factors in a tissue-specific manner. —Claire Olingy [ABSTRACT FROM AUTHOR]