The purpose of this Individually Randomized Group Treatment Trial was to compare an Acceptance and Commitment Therapy-based (ACT) group intervention and a Cognitive Behavioral Therapy-based (CBT) group intervention for weight loss maintenance in a sample of adult patients with obesity seeking treatment for weight loss. One hundred and fifty-five adults (BMI: Kg/m2 = 43.8 [6.8]) attending a multidisciplinary rehabilitation program for weight loss were randomized into two conditions: ACT and CBT. Demographical, physical, and clinical data were assessed at the beginning of the program (t0), at discharge (t1), and at 6-month follow-up (t2). The following measures were administered: The Acceptance and Action Questionnaire-II (AAQ-II) and the Clinical Outcome in Routine Evaluation-Outcome Measure (CORE-OM). Generalized linear mixed models were performed to assess differences between groups. Moderation effects for gender and Eating Disorders (ED) have been considered. From baseline to discharge, no significant differences between interventions were found, with the only exception of an improvement in the CORE-OM total score and in the CORE-OM subjective wellbeing subscale for those in the CBT condition. From discharge to follow-up, ACT group participants showed significant results in terms of weight loss maintenance, CORE-OM total score, and CORE-OM and AAQ-II wellbeing, symptoms, and psychological problems subscales. Gender moderated the effects of time and intervention on the CORE-OM subscale reporting the risk for self-harm or harm of others. The presence of an eating disorder moderated the effect of time and intervention on the CORE-OM total score, on the CORE-OM symptoms and psychological problems subscales, and on the AAQ-II. Patients who received the ACT intervention were more likely to achieve a ≥5% weight loss from baseline to follow-up and to maintain the weight loss after discharge. The ACT intervention was thus effective in maintaining weight loss over time.