Background: Loneliness and social isolation have both been found to be associated with increased mortality in previous studies. One potential underlying mechanism is via the hypothalamic-pituitary-adrenal axis. Objective: This study aimed to examine the association between social network size and cortisol, to analyze the associations between both loneliness and social network size and mortality, and to examine to what extent the association between network size and/or loneliness and mortality is mediated by cortisol. Design: The study group consisted of 443 depressed and non-depressed participants of the Netherlands Study of Depression in the Elderly (NESDO). Cross-sectional analysis of the association between social network size and cortisol measures was followed by a survival analysis of the associations between both social network size and loneliness and mortality. Results: There were no significant associations between social network size and cortisol measures. Loneliness and small social network size were not associated with mortality. Age and partner status were more important predictors of mortality. Conclusion: As people grow older the variety of factors that influence mortality risk increases, diminishing the effect of a single factor. Prevention of early morbidity and mortality in older adults should be tailored to specific needs and risks, instead of aiming at one specific factor.