Background. Previous research has shown prospectively that religiosity/spirituality protects against depression, but these findings are commonly critiqued on two grounds, namely: 1) apparent religiosity/spirituality reflects merely an original absence of depression or elevated mood and 2) religiosity/spirituality too often is measured as a global construct. The current study investigates the relationship between depression and religiosity/spirituality by examining its multidimensional structural integrity. Method. Confirmatory factor analyses with a previously observed cross-cultural factor structure of religiosity/spirituality variables were conducted on an independent sample, diagnostic and familial risk subgroups from this sample, and a subsample of the original cross-cultural sample. Linear regressions onto a previous diagnosis of major depressive disorder (MDD) five years prior to assess potential attenuating impact of a previous depression were explored.Results. Across familial risk groups and clinical subgroups, each of the previously validated religiosity/spirituality domains was confirmed, namely: religious/spiritual commitment, contemplative practice, sense of interconnectedness, experience of love, and altruistic engagement. Previous MDD diagnosis was associated with lower religious/spiritual commitment among high risk individuals, higher contemplation among low risk individuals, and lower importance of religion or spirituality regardless of risk group. Conclusions. Structural integrity was found across familial risk groups and diagnostic history for a multidimensional structure of religiosity/spirituality. Differential associations between a previous diagnosis of MDD and level of religiosity/spirituality across domains suggest a complex and interactive relation between depression, familial risk, and religiosity/spirituality. Accounting for an empirically valid, multidimensional understanding of religiosity/spirituality may advance research on mechanisms underlying the relationship between religiosity/spirituality and mental health.