We investigated whether social relations buffer the effect of neighborhood deprivation on mental and physical health-related quality of life. Baseline data from the LifeLines Cohort Study (N=68,111) and a neighborhood deprivation index were used to perform mixed effect linear regression analyses. Results showed that fewer personal contacts (b, 95%CI: −0.88(−1.08;−0.67)) and lower social need fulfillment (−4.52(−4.67;−4.36)) are associated with lower mental health-related quality of life. Higher neighborhood deprivation was also associated with lower mental health related quality of life (−0.18(−0.24;−0.11)), but only for those with few personal contacts or low social need fulfillment. Our results suggest that social relations buffer the effect of neighborhood deprivation on mental health-related quality of life.