Background: The hypothalamic-pituitary-adrenal (FIFA) axis is the main neuroendocrine system that controls stress responses, including fear learning. To further understand the correlation between the HPA axis and stress and fear-related symptoms in humans, the current study investigated the relationship between HPA axis gene polymorphisms and a stress- and fear-related disorder, posttraumatic stress disorder (PTSD). This is the first study that systematically investigates the correlations between HPA axis genes and distinct PTSD symptom clusters. Methods: Participants included 1132 Chinese earthquake survivors (772 women and 360 men). PTSD symptoms were measured by the PTSD Checklist for DSM-5 (PCL-5), and the severity (total symptoms) and symptom clusters were calculated according to the hybrid seven-factor model of DSM-5 PTSD. We genotyped eight single nucleotide polymorphisms (SNPs) of three HPA axis genes, including FKBP5, CRHR1 and CRHR2. Results: The main effects of the CRHR2 SNP rs2267715 were associated with PTSD severity (P = 0.0035) and all PTSD symptom clusters except dysphoric arousal (P ranging from 0.0011 to 0.048). In women, a gene environment interaction (G x E) effect of FKBP5 (rs3800373 x trauma exposure) was correlated with PTSD severity (P = 0.038), externalizing behaviors, anxious arousal and dysphoric arousal symptoms (P ranging from 0.014 to 0.028); the G x E effect of CRHR1 (rs4458044 x trauma exposure) was associated with anxious arousal symptoms (P = 0.016). In men, a gene gene interaction (G x G) effect of FKBP5 CRHR1 (rs9470080 x rs4458044) was associated with PTSD severity (P = 0.0091), intrusion, negative affect, externalizing behaviors and anxious arousal (P ranging 0.012-0.049). Conclusion: Our results systematically revealed that the main effects and G x E and G x G effects of some genetic polymorphisms of HPA axis genes are involved in the severity and distinct symptom clusters of PTSD.