OBJECTIVE: This study aims to assess whether secondhand smoke (SHS) exposure has an impact on health-related quality of life (HRQOL) in children with acute respiratory illness (ARI). METHODS: This study was nested within a multicenter, prospective cohort study of children (two weeks to 16 years) with ARI (emergency department visits for croup and hospitalizations for croup, asthma, bronchiolitis, and pneumonia) between July 1, 2014 and June 30, 2016. Subjects were surveyed upon enrollment for sociodemographics, healthcare utilization, home SHS exposure (0 or ≥1 smoker in the home), and child HRQOL (Pediatric Quality of Life Physical Functioning Scale) for both baseline health (preceding illness) and acute illness (on admission). Data on insurance status and medical complexity were collected from the Pediatric Hospital Information System database. Multivariable linear mixed regression models examined associations between SHS exposure and HRQOL. RESULTS: Home SHS exposure was reported in 728 (32%) of the 2,309 included children. Compared with nonexposed children, SHS-exposed children had significantly lower HRQOL scores for baseline health (mean difference –3.04 [95% CI –4.34, –1.74]) and acute illness (–2.16 [–4.22, –0.10]). Associations were strongest among children living with two or more smokers. HRQOL scores were lower among SHS-exposed children for all four conditions but only significant at baseline for bronchiolitis (–2.94 [–5.0, –0.89]) and pneumonia (–4.13 [–6.82, –1.44]) and on admission for croup (–5.71 [–10.67, –0.75]). CONCLUSIONS: Our study demonstrates an association between regular SHS exposure and decreased HRQOL with a dose-dependent response for children with ARI, providing further evidence of the negative impact of SHS.