Introduction: This study examined mediators and moderators of short-term treatment effectiveness from the iQUITT Study (Quit Using Internet and Telephone Treatment), a 3-arm randomized trial that compared an interactive smoking cessation Web site with an online social network (enhanced Internet) alone and in conjunction with proactive telephone counseling (enhanced Internet plus phone) to a static Internet comparison condition (basic Internet). Methods: The analytic sample was N = 1,236 participants with complete 3-month data on all mediating variables. The primary outcome was 30-day point prevalence abstinence (ppa) at 3 months. Recognizing the importance of temporal precedence in mediation analyses, we also present findings for 6-month outcomes. Purported mediators were treatment utilization and changes in psychosocial constructs. Proposed moderators included baseline demographic, smoking, and psychosocial variables. Mediation analyses examined the extent to which between-arm differences in 30-day ppa could be attributed to differential Web site utilization, telephone counseling, and associated changes in smoking self-efficacy and social support for quitting. Effect modification analyses fitted interactions between treatment and prespecified moderators on abstinence. Results: Significant mediators of 30-day ppa were changes in smoking temptations, quitting confidence, and positive and negative partner support, which were strongly associated with increased Web site utilization. The addition of telephone counseling to an enhanced Web site further improved abstinence rates, partly via an association with increased quitting confidence. Baseline smoking rate was the only significant moderator. Conclusions: Increased treatment utilization and associated changes in several psychosocial measures yielded higher abstinence rates. Findings validate the importance of treatment utilization, smoking self-efficacy, and social support to promote abstinence.