Abstract only Introduction. Patients receiving serial outpatient infusion treatment for lymphoma or breast cancer (BC) with potentially cardio-toxic chemotherapeutic regimens may experience declines in left ventricular ejection fraction (LVEF) and exercise capacity. This study sought to determine if a physical activity intervention (PAI) administered during cancer treatment could attenuate deterioration of exercise capacity and LVEF. Methods. Across two NCI funded cancer centers, we randomized (2:1) 34 participants to a home-based PAI or healthy living education intervention (HLI) within 6 weeks of initiating curative therapies for stage I-IV Hodgkin’s, non-Hodgkin’s lymphoma, or stage I-III BC (NCT01719562). Training programs were tailored by treatment and functional status and adapted for remote delivery during COVID-19. Exercise capacity was determined via cardiopulmonary exercise test (peak VO 2 ml/kg/min) and LVEF (%) was determined by magnetic resonance imaging at baseline, 3, and 6 months. Separate linear mixed-effects regression models controlling for baseline values examined changes in peak VO 2 and LVEF by time and treatment group. Results. Demographics were similar between the two arms (PAI vs. HLI, 52.4 16.3 vs. 56.8 12.7 years of age SD; 69% vs. 75% white; and 57.7% vs. 50% female). Peak VO 2 increased at 3 (+1.15 ml/kg/min CI: -1.46 - 3.77) and 6 months (+3.88 ml/kg/min CI: 0.79 - 6.96) in the PAI arm, while the HLI arm increased slightly at 3- (+0.67 ml/kg/min CI: -5.14 - 6.48) but not 6 months (-0.83 ml/kg/min CI: -5.99 - 4.33). LVEF declined slightly at 3 months in the PAI (-2.29% CI: -4.83 - 0.25) but not HLI arm (3.05.% CI: -2.49 - 8.60), while at 6 months, the PAI arm had returned to baseline LVEF (-0.58% CI: -4.30 - 3.14) and the HLI arm declined slightly (-1.76% CI: -7.23 - 3.71). Conclusions. This pilot RCT suggests the importance and utility of home-based physical activity during cancer treatment in protecting against expected declines in exercise capacity and LVEF. These results highlight the need for larger randomized trials that examine the effects of lifestyle interventions administered during treatment to improve quality of life and to support long term cardiovascular health in cancer survivors.