Substance use surveys may use open-ended items to supplement questions about specific drugs and obtain more exhaustive information on illicit drug use. However these questions are likely to underestimate the prevalence of use of specific drugs. Little is known about the extent of such underestimation or the groups most prone to under-reporting. Using data from the 2006 National Survey on Drug Use and Health (NSDUH), a civilian, non-institutionalized population survey of persons aged 12 or older in the United States, we compared drug use estimates based on open-ended questions with estimates from a new set of direct questions that occurred later in the interview. For these drugs, estimates of lifetime drug use based on open-ended questions often were at least seven times lower than those based on direct questions. Among adults identified in direct questions as substance users, lower educational levels were consistently associated with non-reporting of use in the open-ended questions. Given NSDUH's large annual sample size (approximately 67,000 interviews), combining data across future survey years could increase our understanding of characteristics associated with non-reporting of use in open-ended questions and allow drug use trends to be extrapolated to survey years in which only open-ended question data are available.