The prevalence of Autism Spectrum Disorder (ASD) is 1 in 110 persons in the U.S. Both parents of children with ASD are under stress that may impact their health-related quality of life (HRQL) (physical and mental health). The purpose of the current study was to explore the relationship of parenting stress, support from family functioning and the HRQL (physical and mental health) of both parents. Female (n = 64) and male (n = 64) parents of children with ASD completed Web-based surveys examining parenting stress, family functioning, and physical and mental health. Results of a Wilcoxon signed-ranks test showed that female parent discrepant (D) scores between “what is” and “should be” family functioning were significantly larger than male parents, p = .002. Results of stepwise linear regression for the male-female partners showed that (1) higher female caregiving stress was related to lower female physical health (p < .001), (2) a higher discrepancy score in family functioning predicted lower mental health (p < .001), accounting for 31% of the variance for females and (3) male parent personal and family life stress (p < .001) and family functioning discrepant (D) score (p < .001) predicted poor mental health, with the discrepancy score accounting for 35% of the variance. These findings suggest that there may be differences in mothers' and fathers' perceptions and expectations about family functioning and this difference needs to be explored and applied when working with families of children with ASD. (PsycINFO Database Record (c) 2012 APA, all rights reserved)