The Age-Related Eye Disease Study (AREDS), sponsored by the National Eye Institute, was designed to study the natural history and risk factors of age-related macular degeneration (AMD) and cataract, and to evaluate the effect of high doses of antioxidants and zinc on eye disease progression. AMD and cataract are leading causes of visual impairment and blindness in the U.S., with frequency of both diseases increasing dramatically after age 65. Participants were randomly chosen to receive antioxidant or placebo tablets. Blood was drawn annually from a subset of patients, and serum concentrations of 17 different nutritional indicators were measured. Because of the complexity of the analytical methods, and possibility of instrument error due to failure of any one of many component parts, several different instruments were used for most analytes. In addition, to assure that the measurement systems were performing adequately across a wide range of concentrations, multiple control pools were monitored with analyte concentrations at low, medium, and high concentrations. We report here the multi-rule quality control system (MRQCS) used during the later part of the trial (AREDS Phase III). This system was designed to monitor systematic error and random within- and among-run error for analytical runs using 1–3 different quality control pools per run and 1–2 measurements of each pool per run. We demonstrate the features of the MRQCS using quality control (QC) data associated with vitamin C measurements. We also provide operating characteristics to demonstrate how the MRQCS responds to increases in systematic and/or random error. Published in 2008 by John Wiley & Sons, Ltd.