In the general population, there is increasing recognition of the effect of thyroid function on patient-centered outcomes, including health-related quality of life and depression. Although hypothyroidism is highly prevalent in hemodialysis patients, it is unknown whether thyroid status is a risk factor for impaired health-related quality of life or mental health in this population. We examined the association of thyroid status, defined by serum thyrotropin, with health-related quality of life and depressive symptoms over time in a prospective cohort of 450 patients on hemodialysis from 17 outpatient dialysis facilities from May of 2013 to May of 2015 who underwent protocolized thyrotropin testing, Short-Form 36 surveys, and Beck Depression Inventory-II questionnaires every 6 months. We examined the association of baseline and time-dependent thyrotropin categorized as tertiles and continuous variables with eight Short-Form 36 domains and Beck Depression Inventory-II scores using expanded case mix plus laboratory adjusted linear mixed effects models. In categorical analyses, the highest baseline thyrotropin tertile was associated with a five-point lower Short-Form 36 domain score for energy/fatigue (P=0.04); the highest time-dependent tertile was associated with a five-point lower physical function score (P=0.03; reference: lowest tertile). In continuous analyses, higher baseline serum thyrotropin levels (+Δ1 mIU/L) were associated with lower role limitations due to physical health (β=-1.3; P=0.04), energy/fatigue (β=-0.8; P=0.03), and pain scores (β=-1.4; P=0.002), equivalent to five-, three-, and five-point lower scores, respectively, for every 1-SD higher thyrotropin. Higher time-dependent thyrotropin levels were associated with lower role limitations due to physical health scores (β=-1.0; P=0.03), equivalent to a three-point decline for every 1-SD higher thyrotropin. Baseline and time-dependent thyrotropin were not associated with Beck Depression Inventory-II scores. In patients on hemodialysis, higher serum thyrotropin levels are associated with impaired health-related quality of life across energy/fatigue, physical function, and pain domains. Studies are needed to determine if thyroid-modulating therapy improves the health-related quality of life of hemodialysis patients with thyroid dysfunction.