The literature supports a positive relationship between spirituality and health. The relationship between spirituality and distress is an underresearched topic. We investigated the relationship between spiritual experiences (SE) and mental distress within two sociodemographically balanced samples (n = 100) of a spiritually practicing (SP) and a nonpracticing sample (NSP) for two points of measurement (t1; t2). Applying linear regression analysis we compared the influence from SEs, as measured with the Exceptional Experiences Questionnaire (EEQ; Kohls & Walach, 2006), towards mental distress measured by the Brief Symptom Inventory (BSI; Klaiberg, 2002). A strong association between the EEQ (t1) and the BSI (t1, t2) for the NSP (NSP: R2t1 = .36; R2t2 = .27) was found, but only a weak, relatively moderate one for the SP sample (SP: R2t1 = .07; R2t2 = .16). Path analysis revealed that SP seems to buffer deconstructive spiritual experiences (SP: ßt1 = .06 (ns); ßt2 = .18 (ns); NSP: ßt1 = .52 (p < .01); ßt2 = .39 (p < .01)) but not psychopathological experiences (SP: ßt1 = .20 (p = ns); ßt2 = .33 (p < .01); NSP: ßt1 = .18 (p = ns); ßt2 = .31 (p < .01), although no significant relationship was found for positive spiritual experiences and visionary dream experiences for either sample. Our findings suggest that spiritual practice seems to be a potential buffer for distress derived from experiences of ego loss. Correspondingly, the differentiation between experiences of ego loss and psychopathological experiences seems to be pivotal for understanding the intrapersonal effects of SP