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Cancer patients experience many physical and psychosocial problems for which they need support. WebChoice is an Internet-based, interactive health communication application that allows cancer patients to monitor their symptoms and problems, provides individually tailored information and self-management support, e-communication with expert cancer nurses, and an e-forum for group discussion with other patients.The objective of this study was to examine the effects of WebChoice on symptom distress (primary outcome), depression, self-efficacy, health-related quality of life, and social support (secondary outcomes).In this 1-year repeated-measures randomized controlled trial, 325 breast and prostate cancer patients were randomized into 1 experimental group with access to WebChoice and 1 control group who received URLs of publicly available cancer Web sites.Group differences on symptom distress were significant only for the global symptom distress index on the Memorial Symptom Assessment Scale (slope estimate, −0.052 [95% confidence interval, −0.101 to −0.004]; t = 4.42; P = .037). There were no significant group differences on secondary outcomes. Additional analyses showed significant within-group improvements in depression in the experimental group only. In the control group, self-efficacy and health-related quality of life deteriorated significantly over time.This randomized controlled trial is one of the first to evaluate effects of an interactive health communication application to support cancer patients in illness management on symptoms. Although only 1 hypothesis was partially supported, the combined results show a clear trend toward better scores in the intervention group on most outcome measures.If findings can be supported with additional research, WebChoice may become an important tool to support nursing care that can equip cancer patients to better manage their illness.