Background: In a single-arm, open-label, phase 2 study (LOTIS 2, NCT03589469), loncastuximab tesirine (loncastuximab tesirine-lpyl; Lonca) has shown antitumor activity with an acceptable toxicity profile and provides stable or improvement in health-related quality of life (HRQOL) in adult patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) after ≥ 2 prior therapies. This analysis evaluates the impact of Lonca on HRQOL, symptoms, and tolerability stratified by age group. Methods: Patients received Lonca as an intravenous infusion on Day 1 of each 3-week treatment cycle. HRQOL change from baseline scores were summarized for EQ-5D visual analog scale (VAS) and the Functional Assessment of Cancer Treatment-Lymphoma (FACT-Lym) by visit and age group. Symptoms related to non-Hodgkin lymphoma or treatment assessed in the FACT-Lym lymphoma subscale were summarized as well as tolerability reported by patient in item GP5 of FACT-Lym. Analysis was conducted using data collected from study initiation (August 2018) through March 2021. Results: A total of 130 patients with a baseline HRQOL score and at least 1 post-baseline score were included in analysis. The median number of Lonca cycles administered was 4 (range, 1-26) and HRQOL completion rate among patients treated at each cycle was greater than 77% through cycle 13. Of those 130 patients, 57 patients were age < 65 years, 53 patients were 65 to < 75 years, and 20 patients were ≥ 75 years. Change from baseline in EQ-5D VAS and FACT-Lym total was stable or improved over the treatment period across all age groups, including age ≥ 75 years. More patients reported improvement than worsening in symptoms of pain, lumps/swelling, and weight loss compared with baseline for a majority of visits, with greater improvement observed in age group ≥ 75 years. A majority of patients reported “a little bit” or “not at all” when being asked how much was bothered by side effects of treatment and a higher percentage of patients in age group ≥ 75 years reported “not at all” than in younger age groups (e.g., at cycle 4, 24% not at all and 44% a little bit in < 65 years, 42% and 25% in 65 to < 75 years, and 67% and 0% in ≥ 75 years). Conclusions: The overall health state and HRQOL were stable or improved in all age groups of patients treated with Lonca. The older age group (≥ 75 years) reported greater improvement in pain, lumps/swelling, and weight loss and better tolerability to treatment side effect.