Objective: The purpose of this study was to examine the effects of Coenzyme Q10 (CoQ10) supplementation on salivary secretory immunoglobulin A (SIgA) and health-related Quality of Life (QOL) in middle-aged and elderly individuals. Methods: Sixty healthy middle-aged and elderly individuals were assigned randomly to a CoQ10 supplementation group (n = 30) or a placebo supplementation group (n = 30) using a double blind method. Subjects took 150 mg CoQ10 or placebo per day for 8 weeks. Salivary SIgA secretion rate and SF-36 test (physical and mental health-related QOL) were determined before and after the intervention. Results: CoQ10 group showed that a tendency to increase of salivary SIgA secretion rate (p = 0.08), although placebo group did not show significant change. Physical health-related QOL did not significantly change in both groups. Vitality and mental health scores, which were subscale of mental health-related QOL, were significantly increased after the intervention in CoQ10 group (p < 0.05), although placebo group did not show significant change. Conclusion: 8 weeks of CoQ10 supplementation may bolster SIgA-mediated oral immunity and mental health-related QOL in middle-aged and elderly individuals.