Background: Web-based programs have been developed for informal caregivers of people with Alzheimer’s disease (PWAD). However, these programs can prove difficult to adopt, especially for older people, who are less familiar with the Internet than other populations. Despite the fundamental role of usability testing in promoting caregivers’ correct use and adoption of these programs, to our knowledge, this is the first study describing this process before evaluating a program for caregivers of PWAD in a randomized clinical trial. Objective: The objective of the study was to describe the development process of a fully automated Web-based program for caregivers of PWAD, aiming to reduce caregivers’ stress, and based on the user-centered design approach. Methods: There were 49 participants (12 health care professionals, 6 caregivers, and 31 healthy older adults) that were involved in a double iterative design allowing for the adaptation of program content and for the enhancement of website usability. This process included three component parts: (1) project team workshops, (2) a proof of concept, and (3) two usability tests. The usability tests were based on a mixed methodology using behavioral analysis, semistructured interviews, and a usability questionnaire. Results: The user-centered design approach provided valuable guidelines to adapt the content and design of the program, and to improve website usability. The professionals, caregivers (mainly spouses), and older adults considered that our project met the needs of isolated caregivers. Participants underlined that contact between caregivers would be desirable. During usability observations, the mistakes of users were also due to ergonomics issues from Internet browsers and computer interfaces. Moreover, negative self-stereotyping was evidenced, when comparing interviews and results of behavioral analysis. Conclusions: Face-to-face psycho-educational programs may be used as a basis for Web-based programs. Nevertheless, a user-centered design approach involving targeted users (or their representatives) remains crucial for their correct use and adoption. For future user-centered design studies, we recommend to involve end-users from preconception stages, using a mixed research method in usability evaluations, and implementing pilot studies to evaluate acceptability and feasibility of programs. [JMIR Res Protoc 2014;3(3):e46]