Background: Distributing a multiple computer-tailored smoking cessation intervention through the Internet has several advantages for both provider and receiver. Most important, a large audience of smokers can be reached while a highly individualized and personal form of feedback can be maintained. However, such a smoking cessation program has yet to be developed and implemented in the Netherlands. Objective: To investigate the effects of a Web-based multiple computer-tailored smoking cessation program on smoking cessation outcomes in a sample of Dutch adult smokers. Methods: Smokers were recruited from December 2009 to June 2010 by advertising our study in the mass media and on the Internet. Those interested and motivated to quit smoking within 6 months (N = 1123) were randomly assigned to either the experimental (n = 552) or control group (n = 571). Respondents in the experimental group received the fully automated Web-based smoking cessation program, while respondents in the control group received no intervention. After 6 weeks and after 6 months, we assessed the effect of the intervention on self-reported 24-hour point prevalence abstinence, 7-day point prevalence abstinence, and prolonged abstinence using logistic regression analyses. Results: Of the 1123 respondents, 449 (40.0%) completed the 6-week follow-up questionnaire and 291 (25.9%) completed the 6-month follow-up questionnaire. We used a negative scenario to replace missing values. That is, we considered respondents lost to follow-up to still be smoking. The computer-tailored program appeared to have significantly increased 24-hour point prevalence abstinence (odds ratio [OR] 1.85, 95% confidence interval [CI] 1.30-2.65), 7-day point prevalence abstinence (OR 2.17, 95% CI 1.44-3.27), and prolonged abstinence (OR 1.99, 95% CI 1.28-3.09) rates reported after 6 weeks. After 6 months, however, no intervention effects could be identified. Results from complete-case analyses were similar. Conclusions: The results presented suggest that the Web-based ...