OBJECTIVE: The Keep It Off trial evaluated the efficacy of a phone-based weight loss maintenance intervention among adults who had recently lost weight in Minnesota (2007-2010). METHODS: 419 adults who had recently lost >/= 10% of their body weight were randomized to the "Guided"or "Self-Directed" intervention. Guided participants received a 10 session workbook, 10 bi-weekly, eight monthly and six bi-monthly phone coaching calls, bimonthly weight graphs and tailored letters based on self-reported weights. Self-Directed participants received the workbook and two calls. Primary outcomes are weight change and maintenance (regain of <2.5% of baseline body weight). RESULTS: Mixed model repeated-measures analysis examining weight change revealed a significant time by treatment group interaction (p<0.0085). Guided participants regained significantly less weight than the Self-Directed participants at 12 and 24 months. The odds of 24 month maintenance were 1.37 (95% CI: 0.97-2.03) times greater in the Guided than in the Self-Directed group. When maintenance rates were compared across all follow-ups, there was a consistently higher maintenance rate for Guided participants (HR 1.31, 95% CI: 1.12-1.54). CONCLUSIONS: A sustained, supportive phone- and mail-based intervention promotes weight loss maintenance relative to a brief intervention for participants who have recently lost weight.