ObjectiveThe aim of this study was to report the results of five weight‐loss interventions in primary care settings in underserved patients and to compare the level of pragmatism across the interventions using the Pragmatic Explanatory Continuum Indicator Summary (PRECIS‐2) tool.MethodsData from 54 primary care clinics (2,210 patients) were pooled from the Promoting Successful Weight Loss in Primary Care in Louisiana (PROPEL) and Rural Engagement in Primary Care for Optimizing Weight Reduction (REPOWER) cluster‐randomized trials. Clinics were randomized to one of five comparators: PROPEL usual care, PROPEL combination of in‐clinic and telephone visits, REPOWER in‐clinic individual visits, REPOWER in‐clinic group visits, or REPOWER telephone group visits.ResultsAt 24 months, weight loss (kilograms) was −0.50 (95% CI: −1.77 to 0.76), −3.05 (−4.10 to −2.01), −4.30 (−5.35 to −3.26), −4.79 (−5.83 to −3.75), and −4.80 (−5.96 to −3.64) in the PROPEL usual care, REPOWER in‐clinic individual visits, REPOWER telephone group visits, REPOWER in‐clinic group visits, and PROPEL in‐clinic and telephone visits arms, respectively. At 24 months, percentage of weight loss was −0.360 (−1.60 to 0.88), −3.00 (−4.02 to −1.98), −4.23 (−5.25 to −3.20), −4.67 (−5.69 to −3.65), and −4.69 (−5.82 to −3.56), respectively, in the five arms. The REPOWER in‐clinic individual visits intervention was the most pragmatic and reflects the current Centers for Medicare and Medicaid Services funding model, although this intervention produced the least weight loss.ConclusionsClinically significant weight loss over 6 months in primary care settings is achievable using a variety of lifestyle‐based treatment approaches. Longer‐term weight‐loss maintenance is more difficult to achieve.