Hypothyroidism is associated with a decreased health-related quality of life (HRQoL). We hypothesized that individuals with hypothyroidism (defined as use of thyroid hormone (TH)) and especially those having an impaired HRQoL are characterized by a high prevalence of comorbid disorders, and that the impact of hypothyroidism and comorbidity on HRQoL is synergistic. Presence of comorbidity was based on data obtained using structured questionnaires, physical examination, biochemical measurements and verified medication use. Single morbidities were clustered into 14 different disease domains. HRQoL was measured using the RAND-36. Logistic regression analyses were used to determine the effect of TH-use on the odds of having an affected disease domain and a lower score than an age- and sex-specific reference value for HRQoL. TH was used by 4537/147201 participants of the population-based Lifelines cohort with a mean(±SD) age of 51.0±12.8 years (88% females). 85% of the TH-users had ≥1 affected disease domain, in contrast to 71% of non-users. TH-use was associated with a higher odds of 13/14 affected disease domains, independent of age and sex. In a multivariable model, TH-use was associated with a decreased HRQoL across 6/8 dimensions. No significant interactions between TH-use and affected disease domains were observed. TH-users with an impaired HRQoL had significantly more comorbidity than those not having an impaired HRQoL. In this large, population-based study, we demonstrated that TH-users had more comorbidity than individuals not using TH. The co-existence of other chronic medical conditions in subjects with TH-use led to further lowering of HRQoL in an additive manner.