BACKGROUND: We investigated health-related quality of life (HrQoL) in Filipino people undergoing TB treatment, and whether HrQoL was negatively impacted by comorbidity with undernutrition, diabetes (DM) and anaemia. METHODS: Adult participants were enrolled in public facilities in Metro Manila (three sites) and Negros Occidental (two sites). Multivariate linear regression was used to model the four correlated domain scores from a WHOQOL-BREF questionnaire (physical, psychological, social, environmental). A forward-stepwise approach was used to select a final multivariable model with inclusion based on global tests of significance at P < 0.1. RESULTS: In 446 people on drug-susceptible TB treatment, DM and moderate/severe anaemia were not associated with HrQoL. After adjustment for age, sex, education, food insecurity, treatment adherence, inflammation, Category I or II TB treatment, treatment phase, current side effects and inhibited ability to work, moderate/severe undernutrition (body mass index < 17 kg/m2) was associated with lower HrQoL (P = 0.003) with reduced psychological (coefficient: −1.02, 95% CI −1.54 to −0.51), physical (−0.62, 95% CI −1.14 to −0.09) and environmental domain scores (−0.45, 95% CI −0.88 to −0.01). In 225 patients with known HIV status in Metro Manila, HIV was associated with modestly reduced HrQoL (P = 0.014). CONCLUSION: Nutritional status and food insecurity represent modifiable risk factors for poor HrQoL that may be alleviated through interventions.