**Background:** Assistive technologies have become more important owing to the aging population, especially when they foster healthy behaviors. Because of their natural interface, virtual agents are promising assistants for people in need of support. To engage people during an interaction with these technologies, such assistants need to match the users´ needs and preferences, especially with regard to social outcomes.

**Objective:** Prior research has already determined the importance of an agent’s appearance in a human-agent interaction. As seniors can particularly benefit from the use of virtual agents to maintain their autonomy, it is important to investigate their special needs. However, there are almost no studies focusing on age-related differences with regard to appearance effects.

**Methods:** A 2×4 between-subjects design was used to investigate the age-related differences of appearance effects in a human-agent interaction. In this study, 46 seniors and 84 students interacted in a health scenario with a virtual agent, whose appearance varied (cartoon-stylized humanoid agent, cartoon-stylized machine-like agent, more realistic humanoid agent, and nonembodied agent [voice only]). After the interaction, participants reported on the evaluation of the agent, usage intention, perceived presence of the agent, bonding toward the agent, and overall evaluation of the interaction.

**Results:** The findings suggested that seniors evaluated the agent more positively (liked the agent more and evaluated it as more realistic, attractive, and sociable) and showed more bonding toward the agent regardless of the appearance than did students. In addition, interaction effects were found. Seniors reported the highest usage intention for the cartoon-stylized humanoid agent, whereas students reported the lowest usage intention for this agent. The same pattern was found for participant bonding with the agent. Seniors showed more bonding when interacting with the cartoon-stylized humanoid agent or voice only agent, whereas students showed the least bonding when interacting with the cartoon-stylized humanoid agent.

**Conclusions:** In health-related interactions, target group–related differences exist with regard to a virtual assistant’s appearance. When elderly individuals are the target group, a humanoid virtual assistant might trigger specific social responses and be evaluated more positively at least in short-term interactions.