1570 Background: Sidekick Health’s 13-week digital health program was built to support cancer self-management. It was available free of charge to US-based cancer patients through commercial health insurance. The program includes disease education, mindfulness, medication adherence support, and asynchronous messaging with a care manager. We hypothesized that highly engaged users had reduced symptom frequency and severity, and improved quality of life (QoL) outcomes. Methods: In-app data were analyzed for registrations Aug 2021-Jan 2024: n(registered)=1286; n(retained ≥7 days)=795; n(QoL/symptoms)=284. QoL was defined as self-reported sleep quality, energy and stress (10-point scale, ≤4x/week). Symptoms were also self-reported (10-point scale, ≤7x/week). Generalized linear mixed models for repeated measures were used to investigate QoL, symptom frequency and severity changes over the program. Subgroup analysis: weekly iterative k-means clustering into highly- and less-engaged (based on total active days) to mitigate survival bias. Results: Diverse patients from 37 states engaged: mean age 58.0 years (SD=10.5), 71% female; 49% diagnosed <6 months ago, 36% ≥12 months ago; 23% early-stage disease, 26% stable disease, 6% in remission and 2% terminal; 60% received chemotherapy, 24% radiation therapy, and 21% immunotherapy. Most (61%) registered users were active after 7 days and 29% after 90 days. Less-engaged users reported higher mean baseline weight (85.3kg (SD=26.7)) vs highly engaged (76.9kg (SD=18.3); p=0.010) but were otherwise similar (age, gender, height, time since diagnosis and treatment: p>0.05). For QoL, highly engaged users had improved energy (p=0.013) and sleep (p=0.002), but not stress (p=0.164) vs less engaged. A significant time-group interaction for sleep (p<0.001) showed highly engaged users had better sleep, and larger improvements over time vs less-engaged. Overall, users reported fewer symptoms over the program (IRR (95% CI)=0.965 (0.953, 0.978), p<0.001). Symptom frequency decreased significantly for stress (p=0.034) and nausea (p=0.003), but not numbness (p=0.320) or fatigue (p=0.530). Highly engaged users’ symptom severity had a downward trajectory, compared with less-engaged, for fatigue (p=0.044) and nausea (p=0.001), but not stress (p=0.234) or numbness (p=0.680). Conclusions: Theprogram was accessed by a broad patient group and retention was high. Highly engaged users reported improved QoL (energy, sleep) and reduced symptom severity (fatigue, nausea). Total symptom frequency was reduced over the program, as well as for stress and nausea specifically. These findings indicate digital self-management is not only achievable for patients with cancer, but that higher engagement may improve patient-reported outcomes.