Although evidence suggests that social networks reduce the risk of mortality and are negatively associated with severe mental disability, little is known about their relationship to everyday functioning and health-related quality of life (HRQoL). In addition, the importance of social networks in the presence of chronic stress remains unclear. We examined the association between social networks and aspects of mental functioning (mental health, vitality and role-emotional functioning) and the relationship between social networks and mental functioning in the presence of stressors. Multiple linear and logistic regression models were used to examine data in 47,912 middle-aged and older healthy women. The Medical Outcomes Study Shortform Health Survey measured dimensions of quality of life. We observed strong associations between levels of social networks and multivariate-adjusted quality of life scores, particularly in potentially high stress situations. Compared to the most socially integrated, women who were socially isolated had reductions in mental health and vitality scores of 6.5 and 7.4 points, respectively and a 60% increased risk of limitation in role-emotional functioning. Social networks are positively associated with mental functioning in women. This association is strongest for women reporting high levels of home and work stressors.