The identification of markers of mental health illness treatment response and susceptibility using personalized medicine has been elusive. In the context of psychological treatment for anxiety, we conducted two studies to identify psychological phenotypes with distinct characteristics related to: psychological intervention modalities (mindfulness training/awareness), mechanism of action (worry), and clinical outcome (generalized anxiety disorder scale scores). We also examined whether phenotype membership interacted with treatment response (Study 1) and mental health illness diagnosis (Studies 1-2). Interoceptive awareness, emotional reactivity, worry, and anxiety were assessed at baseline in treatment-seeking individuals (Study 1, n = 63) and from the general population (Study 2, n = 14,010). In Study 1, participants were randomly assigned to an app-delivered mindfulness program for anxiety for two months or treatment as usual. Changes in anxiety were assessed 1 and 2 months post-treatment initiation. In studies 1-2, three phenotypes were identified: 'severely anxious with body/emotional awareness' (cluster 1), 'body/emotionally unaware' (cluster 2), and 'non-reactive and aware' (cluster 3). Study 1's results revealed a significant treatment response relative to controls (ps < 0.001) for clusters 1 and 3, but not for cluster 2. Chi-square analyses revealed that phenotypes exhibited significantly different proportions of participants with mental health diagnoses (studies 1-2). These results suggest that psychological phenotyping can bring the application of personalized medicine into clinical settings.Registry name and URL: Developing a novel digital therapeutic for the treatment of generalized anxiety disorder https://clinicaltrials.gov/ct2/show/NCT03683472?term=judson+brewer&draw=1&rank=1 .Trial registration: Registered at clinicaltrials.gov (NCT03683472) on 25/09/2018.