Background: Progression-free survival and objective response rate were significantly improved with T-DM1 vs TPC in TH3RESA. The impact of treatment on quality of life is a key aspect in determining treatment value. Here we present the PRO results from the TH3RESA study. Methods: Patients were randomized 2:1 to T-DM1 (3.6 mg/kg every 21 days) or TPC. Patients were asked to complete the EORTC QLQ-C30 (a 30-item questionnaire assessing symptom bother, functioning and health status) and the EORTC QLQ-BM22 (a 22-item survey evaluating pain from bone metastases) at the start of each cycle. Data from patients with a baseline and ≥1 post-baseline assessment were included; a clinically meaningful difference was defined as ≥10 points. Time to pain progression (TPP) was assessed using the Kaplan-Meier method and Cox proportional-hazards models. Results: A greater proportion of patients in the T-DM1 arm (n=297) vs. the TPC arm (n=117) experienced a clinically meaningful improvement in global health status (57.8% [95% CI; 52.0–63.3] vs. 47.1% [95% CI; 38.4–56.4]). The most bothersome symptoms in the T-DM1 arm as measured by the EORTC QLQ-C30 were fatigue and pain. Over the first 10 T-DM1 treatment cycles, 19–30% of patients reported being impacted “quite a bit” or “very much” by fatigue, and 16–25% by pain. Nausea/vomiting and diarrhea were perceived as more tolerable, with 1–5% and 1–4% of patients reporting “quite a bit” or “very much” impact, respectively. TTP was 2.9 months in the T-DM1 arm vs 3.6 months in the TPC arm, but was not significantly different (HR 1.12 [95% CI; 0.82–1.52], p = 0.495). Mean baseline EORTC QLQ-BM22 pain scores were similar in the T-DM1 (n = 306) and TPC arms (n = 130); (25.4 ± 23.8 [SD]) and (27.3 ± 24.4), respectively. There were no clinically meaningful changes in pain levels from baseline over time in either arm. Conclusions: For patients on T-DM1, the most impactful symptoms were fatigue and pain, while the least bothersome were diarrhea and nausea/vomiting; distribution of severity of impact was relatively stable over the first 10 cycles of treatment. TPP was similar between the T-DM1 and TPC arms. Clinical trial information: NCT01419197.