Background: The targeted application and design of digital health interventions (DHIs) require an understanding of usage determinants. Usage includes uptake (initial use) and frequency (extent of use), but it is unclear whether both components are driven by the same determinants. Objective: This study aimed to examine the determinants of uptake and frequency of use and assess whether they differ. Methods: The investigated DHI was a web portal provided in an intervention for improving disease-related self-management. This study is a secondary analysis of intervention group data from a parallel-group randomized controlled trial. Eligibility criteria were being an adult and being diagnosed with type 2 diabetes and/or coronary heart disease. Sociodemographic, psychological, and health-related variables were examined as determinants. Determinants were analyzed using simple and multiple regression models. Uptake was analyzed using logistic regression, and frequency was analyzed using negative binomial regression with robust SEs. Frequency was analyzed for those who used the DHI at least once. Except for sociodemographic variables, all other variables were standardized to a range from 0 to 1. For simple regression, inflation of the α error due to multiple testing was controlled via the approach of Benjamini and Hochberg, and for multiple regression, it was controlled via the significance of the complete multiple regression model. Results: Of 462 intervention group members, 199 (43.1%) used the web portal at least once. After controlling for inflation of the α error, simple regression for uptake yielded significant effects for higher education (B=0.56, 95% CI 0.18-0.95; =.004), openness (B=1.08, 95% CI 0.33-1.83; =.005), intention regarding physical activity (B=2.28, 95% CI 1.30-3.26;