The objective of this study was to examine potential neural substrates that underlie the interplay between religiosity/spirituality (R/S) and risk-for-depression. A new wave of data from a longitudinal, 3 generation study of individuals at high risk for depression is presented. In addition to providing new longitudinal data, we extend previous findings by employing additional (surface-based) methods for examining cortical volume. Magnetic resonance imaging (MRI) scans were collected on 106 second and third generation family members at high or low risk for major depression defined by the presence or absence of depression in the first generation. R/S measures were collected at the same time as the MRI scans and comprised self-report ratings of personal importance and frequency of religious attendance. Analyses were carried out with Freesurfer. Interactive effects of R/S and risk-for-depression were examined on measures of cortical thickness and cortical surface area. A high degree of belief in the importance of R/S was associated with both a thicker cortex and a larger pial surface area in persons at high risk for familial depression. No significant association was found between cortical regions and religious attendance in either risk group. The results support previous findings of an association between R/S importance and cortical thickness in individuals at high risk for depression, and extend the findings to include an association between R/S importance and greater pial surface area. Moreover, the findings suggest these cortical changes may confer protective benefits to R/S individuals at high risk for depression.