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Objective: Lifestyle interventions have had limited effectiveness in work sites when evaluated in randomized trials. This study assessed the effectiveness of a novel lifestyle intervention for weight loss (Healthy Weight for Living [HWL]) implemented with or without meal replacements (MR) in work sites. HWL used a new behavioral approach emphasizing reducing hunger and building healthy food preferences, and, unlike traditional lifestyle interventions, it did not require calorie counting., Methods: Twelve work sites were randomized to an 18-month intervention (n = 8; randomization within work sites to HWL, HWL + MR) or 6-month wait-listed control (n = 4). Participants were employees with overweight or obesity (N = 335; age = 48 [SD 10] years; BMI = 33 [6] kg/m 2 ; 83% female). HWL was group-delivered in person or by videoconference. The primary outcome was 6-month weight change; secondary outcomes included weight and cardiometabolic risk factors measured at 6, 12, and 18 months in intervention groups., Results: Mean 6-month weight change was -8.8% (95% CI: -11.2% to -6.4%) for enrollees in HWL and -8.0% (-10.4% to -5.5%) for HWL + MR (p < 0.001 for both groups vs. controls), with no difference between interventions (p = 0.40). Clinically meaningful weight loss (≥5%) was maintained at 18 months in both groups (p < 0.001)., Conclusions: A new lifestyle intervention approach, deliverable by videoconference with or without MR, supported clinically impactful weight loss in employees., (© 2023 The Obesity Society.)