Background. Many studies have shown correlation between heterozygosity and fitness; particularly when organism is exposed to stress or when environmental conditions are detrimental. ----- The aim of this study was to investigate if standardized multi-locus heterozygosity is associated to morning cortisol concentration in response to acute psychological distress. Additional aim of the study was to perform genome-wide association study (GWAS) of cortisol, in order to identify genetic factors that affect cortisol concentration. ----- Methods. Custom-made questionnaire was used to collect general and lifestyle information of 924 study participants from the island of Vis. GHQ-30 was used to assess participants’ psychological state. DNA was extracted from blood and all samples were genotyped with STR and SNP markers. Standardized multilocus heterozygosity was calculated from the proportion of heterozygous STR markers for each individual. ----- Results. Multivariate analysis has shown statistically significant association of age, BMI, education, psychological distress and heterozygosity to cortisol concentration. Standardized multilocus heterozygosity is inversely associated to morning cortisol concentration (p=0.005). Genome-wide association study of cortisol has revealed a suggestive association of rs1000772 to morning cortisol concentration (p<0.00001). Searching the Ensembl database revealed that this SNP marker is located on chromosome 3p25.3 near GHRL. Literature search revealed that this gene codes for hormone ghrelin that is involved in regulation of cortisol secretion. -----Conclusion. Individuals with lower standardized multi-locus heterozygosity exhibit greater deviation in cortisol concentration following acute psychological distress (higher values), while the deviation from the normal values is smaller in more heterozygous individuals. These results suggest the possibility that more heterozygous individuals have a better ability to compensate psychological distress and better ability to retain homeostasis; hence they may also exhibit better fitness. There is suggestive evidence that SNP rs1000772 affects GHRL gene expression and thereby affects cortisol concentration, but additional studies are required.