Background Missing cases present a challenge to our ability to evaluate the effects of web-based psychotherapy trials. As missing cases are often lost to follow-up, less is known about their characteristics, their likely clinical outcomes, or the likely effect of the treatment being trialed. Objective The aim of this study is to explore the characteristics of missing cases, their likely treatment outcomes, and the ability of different statistical models to approximate missing posttreatment data. Methods A sample of internet-delivered cognitive behavioral therapy participants in routine care (n=6701, with 36.26% missing cases at posttreatment) was used to identify predictors of dropping out of treatment and predictors that moderated clinical outcomes, such as symptoms of psychological distress, anxiety, and depression. These variables were then incorporated into a range of statistical models that approximated replacement outcomes for missing cases, and the results were compared using sensitivity and cross-validation analyses. Results Treatment adherence, as measured by the rate of progress of an individual through the treatment modules, and higher pretreatment symptom scores were identified as the dominant predictors of missing cases probability (Nagelkerke R2=60.8%) and the rate of symptom change. Low treatment adherence, in particular, was associated with increased odds of presenting as missing cases during posttreatment assessment (eg, odds ratio 161.1:1) and, at the same time, attenuated the rate of symptom change across anxiety (up to 28% of the total symptom with 48% reduction effect), depression (up to 41% of the total with 48% symptom reduction effect), and psychological distress symptom outcomes (up to 52% of the total with 37% symptom reduction effect) at the end of the 8-week window. Reflecting this pattern of results, statistical replacement methods that overlooked the features of treatment adherence and baseline severity underestimated missing case symptom outcomes by as much as 39% at posttreatment. Conclusions The treatment outcomes of the cases that were missing at posttreatment were distinct from those of the remaining observed sample. Thus, overlooking the features of missing cases is likely to result in an inaccurate estimate of the effect of treatment.