Abstract Background: Obesity and physical inactivity increase the risk of many types of cancer. Effective weight management, healthy diet, and physical activity are critical to reduce cancer risk. This pilot study of a technology-based weight loss program evaluated the program feasibility, weight loss, and improvement of healthy behaviors and quality of life among minority and medically underserved participants with obesity for cancer prevention. Methods: Participants in this pilot study were included from four cohorts: 1) Mano a Mano Mexican American Cohort (MAC; family dyads) 2) Project CHURCH (African-American men), 3) High- Risk Breast Cohort (HRBC; women), and 4) Mammography Cohort (women who participated in mammography screening). A 16-week weight loss program using the Diabetes Prevention Program was provided for healthy eating, physical activity, and portion control. Participants received program materials, text messages, Fitbit, and Wi-Fi connected scale. Weight, physical activity, dietary intake, weight-related health behaviors, and quality of life were assessed at baseline and follow-up. Program feasibility including retention and satisfaction were assessed after the program. Changes in outcomes from pre- to post- program were examined using paired t-tests and chi-squared tests. Results: Among 48 enrolled participants, 37 participants completed the program (total=77%; MAC=59%; Project CHURCH=90%; HRBC=90%; Mammography=90%). During the program, 46% participants measured and recorded their weights at least one day per week (MAC=17%; Project CHURCH=60%; HRBC=80%; Mammography=50%); 65% wore the Fitbit at least 2 days per week (MAC=44%; Project CHURCH=90%; HRBC=80%; Mammography=60%); 77% responded to text messages 15 out of 30 times (MAC=61%; Project CHURCH=90%; HRBC=90%; Mammography=80%); and 92% were satisfied with the program (MAC=100%; Project CHURCH=100%; HRBC=78%; Mammography=89%). After the program, we observed about 2% weight loss in average (self- report: p=0.009; scale measured: p=0.010). There were significant improvements in weight- related eating behaviors (routine restraint: +0.55, p=0.001; compensatory restraint: +0.49, p=0.001; susceptibility to external cues: -0.41, p=0.026; and emotional eating: -0.57, p=0.001). Stage of change for weight control showed significant shifts from action to maintenance stage (p=0.012). Furthermore, dietary habits significantly changed after the intervention with decreased 30% of total energy intake (p<0.001), increased 14% protein intake (p=0.044), and decreased 56% added-sugar intake (p<0.001). Conclusions: This digital weight loss program was determined as feasible and effective for weight loss and improving eating behaviors and dietary intake among minority and medically underserved individuals with obesity. The MAC showed a higher drop-out rate and less engaged in the program compared to other cohort, and therefore, this cohort may need adapted and more support that a low touch digital weight loss program can provide to improve the feasibility. Citation Format: Che Young Lee, Thuan Le, Carrie R Daniel, Larkin L. Strong, Scherezade K Mama, Lorna H McNeill, Abenaa Brewster, Samir Hanash, Karen Basen-Engquist. A pilot study of a digital weight loss program for cancer prevention among obese individuals from four diverse cohorts [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr B053.