The Internet provides a medium to administer and evaluate evidence-based interventions for highly prevalent public health problems worldwide. The authors report a series of four Internet smoking cessation studies conducted in English and Spanish. These studies examined both outcome (self-reported 7-day abstinence) and mechanisms related to outcome (the impact of major depressive episodes [MDEs] on the likelihood of quitting). Over 4,000 smokers from 74 countries entered the studies. Studies 1 and 2 evaluated a standard smoking cessation guide (the "Guía"). Studies 3 and 4 were randomized trials comparing the Guía+ITEMs (individually timed educational messages) to the Guía+ITEMs+a mood management course. ITEMs were E-mails inviting participants back to the site at specific times. Online follow-up assessments resulted in completion rates of 44%-54% at 1 month and 26%-30% at 6 months in studies 1 and 2. Incentives and follow-up phone calls increased these rates to 70%, 66%, 65%, and 62% at 1, 3, 6, and 12 months in study 4. At 6 months, self-reported 7-day abstinence rates using missing = smoking data were 6% in studies 1 and 2, 10%-14% in study 3, and 20%-26% in study 4. The Guía+ITEMs condition tended to have higher quit rates, which reached significance at the 12-month follow-up in study 3 and at the 3-month follow-up in study 4. Smokers with past (but not current) MDEs tended to be the most likely to abstain and those with current MDEs the least likely. This trend reached significance in studies 1 and 4.