Although evidence-based psychotherapies, such as cognitive behavioral therapy (CBT) and interpersonal psychotherapy (IPT), produce comparable average outcomes, it is plausible that some patients who possess one or more specific characteristics may respond better to one over the other. Addressing this what works best for whom question, researchers have tested the moderating influence of patient characteristics on comparative treatment effects (viz. aptitude-treatment interactions [ATIs]). However, few ATIs have emerged or replicated, thereby providing little treatment-selection guidance. Informed by a systematic review of patient ATIs in trials that compared CBT versus IPT for depression (Bernecker et al., 2017), this study aimed to replicate (a) significant ATIs previously established in a single study; and (b) significant ATIs previously examined twice, with only one study demonstrating a moderating effect. Data derived from a trial in which adult outpatients with major depression were randomly assigned to 16 weeks of CBT (n = 41) or IPT (n = 39). Patient characteristics were measured at baseline, and patients rated their depression throughout treatment. Multilevel models revealed one ATI replication; for patients with more self-sacrificing interpersonal problems, CBT outperformed IPT; the reverse was true for patients with fewer such problems. Other moderators either failed to replicate or directionally contradicted prior research. Results help inform optimal treatment matching for some patients, which reflects a type of psychotherapy personalization. However, they also highlight limitations of traditional ATI research and suggest that different methods are needed to inform responsive personalization efforts more expansively and reliably. (PsycInfo Database Record (c) 2022 APA, all rights reserved).