Self-disclosure is purposeful disclosure of personal information to other people, and online self-disclosure on health-related issues is important in promoting a safe and sound online health environment. The present study investigates the ways in which youths engage in online self-disclosure of health-related issues in the Web 2.0 age. We examine how self-disclosure is driven by the level of trust in social media and uncertainty reduction actions, i.e., seeking information to verify and challenge the prescription after visiting medical professionals. Comparative surveys were conducted in Hong Kong, South Korea, and the U.S., respectively. Compared to their counterparts in South Korea and the U.S., youths in Hong Kong were significantly more likely to disclose personal health issues with peers online. Hong Kong youths also held the highest level of trust towards health-related information on social media. Meanwhile, both the level of trust in social media and uncertainty reduction actions were positively associated with online self-disclosure.