This study investigated inconsistent responding to survey items by participants involved in longitudinal, web-based substance use research. We also examined cross-sectional and prospective predictors of inconsistent responding. Middle school (N = 1,023) and college students (N = 995) from multiple sites in the United States responded to online surveys assessing substance use and related variables in three waves of data collection. We applied a procedure for creating an index of inconsistent responding at each wave that involved identifying pairs of items with considerable redundancy and calculating discrepancies in responses to these items. Inconsistent responding was generally low in the Middle School sample and moderate in the College sample, with individuals showing only modest stability in inconsistent responding over time. Multiple regression analyses identified several baseline variables—including demographic, personality, and behavioral variables—that were uniquely associated with inconsistent responding both cross-sectionally and prospectively. Alcohol and substance involvement showed some bivariate associations with inconsistent responding, but these associations largely were accounted for by other factors. The results suggest that high levels of carelessness or inconsistency do not appear to characterize participants’ responses to longitudinal web-based surveys of substance use and support the use of inconsistency indices as a tool for identifying potentially problematic responders.