Family, twin, and adoption studies have suggested a genetic component to suicidal behavior, although these findings have been based predominantly on populations of European descent. One potential mechanism is through the hypothalamic-pituitary-adrenal (HPA) axis, a major stress regulator. Corticotropin releasing receptor type 1 (CRHR1), 2 (CRHR2), glucocorticoid (NR3C1), and mineralocorticoid (NR3C2) receptor genes play a key role in the activation and modulation of the HPA axis. Childhood trauma is an environmental risk factor associated with suicidal behavior and it has also been shown to be associated with HPA axis dysregulation. Using data collected from two cohorts of participants seen in a psychiatric clinic in Mexico City to assess if there is a synergistic relationship between childhood trauma, including sub-types of trauma, and HPA axis genes, thus conferring an increased risk of suicide attempts in patients with psychiatric disorders. Data was collected on adverse childhood experiences and previous suicide attempts and DNA was extracted from blood. Genotype information was available on six known risk alleles in CRHR1 and CRHR2 in one cohort and five known risk alleles on NR3C1 and NR3C2 in the second cohort, with additional gene expression data available on a sub-sample. This study was conducted in two phases, first assessing a GxE and GxG interaction of selected CRHR1, CRHR2, NR3C1 and NRC3C2 risk alleles and childhood trauma on history of suicide attempt using multifactor dimensional reduction models and second performing an eQTL GxE analysis using comparation between groups carriers of risk alleles. In the first cohort of 366 participant, 183 (50%) of which had at least one suicide attempt, we showed an interaction of genetic variants analyzed of CRHR1 and CRHR2 with CT, thus conferring increased risk of having presented at least one SA (OR = 7.44, 95% CI [4.58 – 12.07], p < 0.0001). In addition, we observed the following in the trauma subtype analysis: physical neglect (OR = 4.72, 95% CI [3.01 – 7.4], p < 0.0001), emotional abuse (OR = 5.76, 95% CI [3.67 – 9.05], p < 0.0001), and sexual abuse (OR = 5.7, 95% CI [3.62 – 8.97], p < 0.0001). In the second cohort of 516 participants, 274 (53%) had at least one suicide attempt we observed a significant interaction of NR3C1 and NR3C2 and any childhood trauma (OR = 2.8, 95% CI [1.9 – 3.9], p < 0.0001). Significant interactions were also observed with neglect (OR = 2.1, 95% CI [1.4 – 3.1], p < 0.0001), emotional abuse (OR = 2.1, 95% CI [1.5 – 3], p < 0.0001), and sexual abuse (OR = 2.4, 95% CI [1.4 – 2.9], p < 0.0001) in association with suicide attempt. Additionally, the analysis of gene expression identified an overexpression of NR3C1 in participants with a history of suicide attempts and with high scores for physical and sexual abuse (p < 0.0001; p < 0.0006, respectively) and emotional neglect (p = 0.014). An under expression was observed of NR3C2, associated with high scores of trauma subtypes (p < 0.0001) except physical neglect. In overview, our findings suggest that genetic variants of these two peptide hormone receptors and two steroid hormone receptors are related to differential expression levels, increasing the risk of a suicide attempt in psychiatric patients with a history of neglect and abuse in childhood. These analyses, while in a small cohort, are the first such analysis in Mexican populations and add further evidence to the role of the HPA axis and childhood trauma in risk of suicide attempts.