Abstract Context Apalutamide (APT) is a nonsteroidal anti-androgen medication used to treat metastatic castrate sensitive and non-metastatic castrate-resistant prostate cancer. Early clinical trials of APT identified thyroid dysfunction as a common adverse effect of therapy, but the clinical presentation and management of APT-induced hypothyroidism has not been studied. Methods We report a case series of 16 patients with APT-associated thyroid dysfunction during prostate cancer treatment at two academic medical centers. Patient clinical parameters, thyroid function laboratory data, and thyroid hormone requirements over the course of APT treatment were analyzed. Results Among the 16 patients in our case series with APT-associated hypothyroidism, 3 had no prior thyroid disease and 13 had pre-existing hypothyroidism. The patterns of thyroid dysfunction included overt and subclinical hypothyroidism. The median time from APT initiation to thyroid function test abnormality was 19 weeks, but occurred in some cases as early as 2-4 weeks. Hypothyroidism was effectively managed with thyroid hormone replacement using levothyroxine (LT4), though some patients with pre-existing hypothyroidism required a 2- to 3-fold dose increase while on APT to achieve euthyroid state. In the subset of patients who completed or stopped APT therapy, TSH fell at a median of 11 weeks post-APT therapy and thyroid hormone requirements decreased to near pre-APT levels. Conclusion APT-associated thyroid dysfunction presents as new or worsening hypothyroidism and should prompt initiation or increase in thyroid hormone replacement. Monitoring of thyroid function tests is recommended every 1-2 months for all patients on APT and 2-3 months after completion of APT.