In obese subjects, the liver may be differentially affected by significant weight loss depending on as yet unknown factors. We explored clinical factors associated with serum alanine aminotransferase (ALT) changes during significant weight loss in a residential weight loss program. Clinical data from 362 adults who received a comprehensive weight loss intervention (ie, diets, physical fitness, and behavioral modification) in the program were analyzed. Serum ALT was used as a surrogate marker of liver injury. The ALT changes during the program were calculated to create study outcome categories (improvement, no change, or deterioration of ALT during significant weight loss). Variables of demography, lifestyle, and comorbidities at baseline, and total/rate of weight change during the program were explored for associations with the ALT change categories using multiple logistic regression models. Variation by sex was apparent among predictors of ALT deterioration; men with rapid weight loss and women with higher initial body mass index were more likely to experience ALT deterioration, whereas men with prior alcohol consumption were less likely to experience ALT deterioration even after adjusting for baseline ALT (Ps < .03). Variation by age was apparent among predictors of ALT improvement; younger patients with current smoking and older patients with rapid weight loss, diabetes or impaired fasting glucose, or sleep apnea or who followed a reduced-carbohydrate diet were less likely to experience ALT improvement (Ps < .05). A number of clinical factors influence ALT changes during weight loss in sex- and age-specific manners. The patterns that we detected may have pathophysiologic significance beyond the practical implications of our findings in clinical practice related to underlying changes in fat metabolism.