Faith factors (i.e., factors pertaining to religion/spirituality) have been linked with well-being and adequate coping. Few studies have investigated negative aspects of religious coping, such as spiritual struggle. Based on the multidisciplinary literature and on previous findings, the study's analysis estimated parallel psychophysiological pathways from preoperative distress to postoperative depression in patients undergoing open heart surgery. Plasma samples for interleukin(IL)-6 were obtained before surgery. The results showed that a link between spiritual struggle and IL-6 mediated the indirect effects of preoperative anxiety on postoperative depression. Avoidant coping also mediated the influence of anxiety on postoperative maladjustment. Further, hope played a protective mediating role to moderate the undesirable influences of the spiritual struggle–IL-6 link and maladaptive coping on postoperative mental health attributes. © 2010 Wiley Periodicals, Inc. J Clin Psychol 66:1–19, 2010.