Background <p>Negative interpretations of ambiguous information are theorized to play a key role in the etiology and maintenance of depression and anxiety. However, empirical tests of these relationships are scarce. The present longitudinal study sought to determine whether negative interpretation bias, positive interpretation bias, and interpretation inflexibility predict changes in depression, social anxiety, and generalized anxiety over time.</p> Methods <p>Undergraduates (<i>N</i> = 152) self-enrolled in the study and completed online self-report measures of depression, social anxiety, and generalized anxiety at baseline as well as at two-week (<i>N</i> = 141) and three-month (<i>N</i> = 122) follow-ups. The emotional Bias Against Disconfirming Evidence task, which measures negative and positive interpretation bias and inflexibility, was also completed at baseline.</p> Results <p>Hierarchical regression analyses revealed that negative interpretation bias was predictive of increased depressive symptomatology at both two-week and three-month follow-ups. Conversely, positive interpretation bias predicted lower social anxiety at both follow-ups. Similar to depression, negative interpretation bias was significantly associated with increased generalized anxiety at the two-week follow-up. Additionally, positive interpretation bias was associated with decreased generalized anxiety at the three-month follow-up.</p> Conclusions <p>These results support the role of interpretation biases in the etiology and maintenance of depression, social anxiety, and generalized anxiety and suggest potential targets for clinical intervention.</p>