This study aimed at exploring to what extent psychosocial factors, such as religiosity/spirituality and sense of coherence, mediate the negative effects of stress on a variety of cardiometabolic indicators, i.e., hypertension, diabetes, cardiovascular and cerebrovascular disease, and atherosclerotic bio-clinical markers.A total of 220 subjects (66.2±16.0 years) of the SPILI III cohort (1988-2012) attending a primary care setting in Spili, a rural town in Crete, represented the target group for the present study. Of these, 195 (88.6%) participated in the re-examination (67.2±15.2 years). All participants underwent a standardized procedure including evaluation of anthropometric measurements, biochemical indicators of atherosclerosis, stress hormones, in parallel with ultrasound measurements of carotid intima media thickness (IMT). Religiosity, spirituality and sense of coherence were evaluated with the use of international questionnaires translated into the Greek language and linguistically validated.Participants with higher levels of religious and spiritual beliefs presented lower levels of carotid IMT (1.01±0.101 vs 1.53±0.502 mm, p<0.001). Patterns of inverse relationships were also observed between religiosity/spirituality and prevalence of diabetes (35.1% vs. 2%, p<0.001) with an estimated diabetes risk, fully adjusted odds ratio, 95% CI: 0.91 (0.87-0.94). Highly religious participants presented lower serum cortisol levels (12.3±5.8 vs. 18.2±5.1 μg/dl, p<0.001). Sense of coherence was positively associated with religiosity/spirituality [mean SOC (SD): 123±20 vs. 158±15) p<0.001].These findings may be associated with a possible favourable effect of religiosity/spirituality on several cardio-metabolic determinants, therefore deserving further attention by healthcare practitioners and researchers.