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BACKGROUND: The impact of employment and the work-from-home (WFH) setting on body weight among people with obesity is unknown. OBJECTIVE: This study examined the relationship between employment status, WFH setting, and change in body weight among adults with obesity during the COVID-19 pandemic. METHODS: Patients from an obesity medicine clinic completed an online survey in 2022 to assess health, work, and lifestyle behaviors. Multiple regression models examined the association between WFH status and change in body weight. RESULTS: The analytical sample included 380 patients (81.9% female, mean age 52.5 years, mean body mass index 43.25, 50.0% non-Hispanic White, 25.7% non-Hispanic Black, 18.7% Hispanic, 5.7% other ethnicity). During the pandemic, 28.7% were employed in a WFH setting (73.4% of this subgroup were in a WFH setting only), 36.1% were employed but not in a WFH setting, 11.8% were unemployed, and 23.4% were retired. Mean body weight change for participants who partially WFH during the pandemic was +5.4 (±7.2) % compared to those completely WFH –0.3 (±9.8) % (P = 0.006). After adjusting for key demographics, participants who were partially WFH gained 7.8% more weight compared to those completely WFH (β= 7.28, SE = 1.91, p < 0.001). The most significant predictors for weight gain after adjusting for WFH frequency (partially vs. completely) included overeating (aOR 11.07, 95% CI 3.33–36.77), more consumption of fast food (aOR 7.59, 95% 2.41–23.91), and depression (aOR 6.07, 95% CI 1.97–18.68). CONCLUSION: These results show that during the COVID-19 pandemic, the WFH hybrid (combination of office and WFH) setting is associated with greater weight gain compared to those who completely WFH in people with obesity. Risk factors include overeating, higher fast food consumption, and depression. [ABSTRACT FROM AUTHOR]