CONTEXT: The effectiveness of dietary modification in reducing low-density lipoprotein cholesterol (LDL-C) levels can be reliably predicted for populations, but not for individuals. OBJECTIVE: To determine whether individual variation in cholesterol response to dietary modification is a familial trait. DESIGN: Two-period, outpatient crossover trial conducted from September 1997 to September 1999. SETTING AND PARTICIPANTS: Fifty-six families from the Dallas-Ft Worth, Tex, area with 2 biological parents and at least 2 children aged 5 years or older volunteered; 46 families (n = 92 adults and n = 134 children) completed the study. INTERVENTION: All families followed two 5-week dietary regimens that included individualized daily dietary prescriptions and emphasized a low-saturated fat diet supplemented with specially manufactured baked goods and spreadable fat. One regimen used butter only and the other used margarine only. MAIN OUTCOME MEASURE: Mean LDL-C levels during the last 2 weeks of each dietary period. RESULTS: Margarine intake compared with butter intake lowered LDL-C levels 11% in adults (95% confidence interval [CI], 13% to 9%) and 9% in children (95% CI, 12% to 6%) (P<.001 for both adults and children). The distribution of individual responses were peaked around the mean response. For adults and children together, family membership accounted for 19% of variability in response (P =.007). In children, family membership accounted for 40% of variability in response of percent change in LDL-C levels (P =.002). Body mass index and change in cholesterol ester (CE) 18:2/18:1 ratio accounted for 26% of variation, leaving 26% still attributable to family membership. In all participants, BMI predicted response-heavier individuals had higher LDL-C levels, less excursion in CE fatty acids, and less LDL-C response to dietary change. CONCLUSIONS: Our results suggest that individual variation in response to a cholesterol-lowering diet is a familial trait. Body weight is an important modifiable factor that influences response. JAMA. 2000;284:2740-2747.