Computerized ambulatory monitoring overcomes a number of methodological and conceptual challenges to studying mental disorders, however concerns persist regarding the feasibility of this approach with severe psychiatric samples and the potential of intensive monitoring to influence data quality. This multi-site investigation evaluates these issues in four independent samples. Patients with schizophrenia (n = 56), substance dependence (n = 85), anxiety disorders (n = 45), and a non-clinical sample (n = 280) were contacted to participate in investigations using computerized ambulatory monitoring. Micro-computers were used to administer electronic interviews several times per day for a one-week period. Ninety-five percent of contacted individuals agreed to participate in the study, and minimum compliance was achieved by 96% of these participants. Seventy-eight percent of all programmed assessments were completed overall, and only 1% of micro-computers were not returned to investigators. There was no evidence that missing data or response time increased over the duration of the study, suggesting that fatigue effects were negligible. The majority of variables investigated did not change in frequency as a function of study duration, however some evidence was found that socially sensitive behaviors changed in a manner consistent with reactivity.