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.