PURPOSE: In the fear-avoidance model (FAM) of chronic pain, pain-related fear is one of the most prominent predictors of negative adjustment outcomes. While existing data point to the effects of anxiety sensitivity, pain hypervigilance, and pain catastrophizing on pain-related fear, the nature of their multivariate relationships remains unclear. This study explored the possible mediating role of pain hypervigilance in the relationship of anxiety sensitivity and pain catastrophizing with pain-related fear, and their effects on quality of life (QoL) outcomes within the FAM framework. METHODS: A sample of 401 Chinese patients with chronic musculoskeletal pain completed the standardized measures assessing the FAM components and QoL. Structural equation modeling (SEM) was used to evaluate six hypothesized models. RESULTS: Results of SEM showed adequate data-model fit [comparative fit indexes (CFIs) ranging from 0.92 to 0.94] on models which specified pain hypervigilance as mediator of anxiety sensitivity and pain catastrophizing with pain-related fear on two QoL outcomes (QoL-Physical and QoL-Mental). Results consistent with net suppression effects of pain catastrophizing on anxiety sensitivity were found in SEM when both anxiety sensitivity and pain catastrophizing were included in the same full model to predict QoL-Physical (CFI = 0.95; Sobel z = 8.06, p < 0.001) and QoL-Mental (CFI = 0.93; Sobel z = 8.31, p < 0.001). CONCLUSIONS: These cross-sectional analyses gave results consistent with pain hypervigilance, mediating the relationship of pain catastrophic cognition and anxiety sensitivity with pain-related fear. The net suppression effects of pain catastrophizing point to anxiety sensitivity, enhancing the effect of pain catastrophic cognition on pain hypervigilance. These findings elucidate how the interdependence of dispositional factors might influence pain adjustment and functioning.