Background: The prevalence of type 2 diabetes mellitus (T2DM) is rising in the Netherlands, and health care’s workload will increase. e-Health applications may increase patients’ participation in their care and could help reducing workload. To explore potential users, differences in patients interested and uninterested in e-Health are characterized. Methods: A prospective cohort study was initiated in the Drenthe region of the Netherlands. This study included inviting T2DM patients to use e-Health (the e-Vita platform). Patients were offered access to clinical data, laboratory results, educational modules, and a self-management support program. Data were obtained from health record systems of general practices and questionnaires. Results: Out of 2674 patients, 1378 (51.5%) participated in the study. Of the 1378 patients, 974 (70.7%) were interested in e-Health. Of 974, 405 (41.6%) were registered for e-Health. Interested patients were more often male, were younger, had shorter T2DM duration, and were higher educated. Of 405, 110 (27.2%) used the e-Health. No differences were found between users and nonusers of e-Health. Discussion: Patients interested in e-Health were more often male, were younger, had shorter T2DM duration, and were more often higher educated. However, even in this interested group, the actual participation rate remained low. Together with characteristics and attitudes of caregivers and T2DM patients, the look and content of the e-Health platform strategies that increase interest and participation need to be developed.