Background: The relationship between food insecurity and mental and physical components of health-related quality of life (HRQOL) has been less addressed by healthcare professionals. Objective: We aimed to investigate the relationship between household food insecurity and mental and physical components of HRQOL in a large sample of urban people and to determine whether household food insecurity has a negative effect on mental and physical components of HRQOL. Methods: This cross-sectional study was conducted across twenty-two districts of Tehran (capital of Iran) during 2011. The participants were selected through multistage cluster random sampling. Two questionnaires were used to measure household food insecurity and HRQOL in the study population, while descriptive and inferential statistics were applied to test the relationships between these two parameters. Results: The mean age of the study population was 44.5 ± 15.5 years and most were female (64.8%). The results of this study indicated an independent relationship between household food insecurity and different subscales of HRQOL (P<0.001). Household food insecurity had a significant negative relationship with physical (β= -5.93; P<0.001) and mental (β= -6.54; P<0.001) summary scores of HRQOL. Likewise, average scores on all subscales of HRQOL according to household food security status were significantly different (P<0.001). Conclusion: Food insecurity was associated with mental and physical components of HRQOL among urban participants and can be considered as a part of comprehensive interventions that target to improve general health.