Although previous studies have examined selected factors influencing health promoting behaviors or quality of life, the complex interplay of these variables in persons with different chronic disabling conditions has not been investigated. This study tested an explanatory model of variables influencing health promotion and quality of life originally developed with a sample of persons with multiple sclerosis in a new sample of persons living with post-polio syndrome (PPS) in the USA. The sample of 1603 persons with PPS (1123 females, 478 males and 2 unknown) completed a battery of instruments including measures of severity of polio-related impairment, barriers to health promoting behaviors, resources, self-efficacy, acceptance, health promoting behaviors and perceived quality of life. A model originally developed in a sample of 786 persons with multiple sclerosis was assessed and modified using the weighted least squares procedure (WLS) which is implemented by LISREL8. The structural equation analyses resulted in a proper solution that exhibited adequate fit: chi2 (8, N = 1549)=84.22, p<0.05; GFI=0.96, IFI=0.90, CFI=0.90. The antecedent variables accounted for 65% of the variance in the frequency of health promoting behaviors and 53% of the variance in perceived quality of life. The model test supports the hypothesis that quality of life is the outcome of a complex interplay between contextual factors (severity of impairment), antecedent variables, and health promoting behaviors. It also suggests that the relationships among these variables are similar in samples of persons with two different chronic conditions. Further research using a qualitative approach is needed to clarify other contributors to quality of life in persons with post-polio syndrome.