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Psychological interventions for delusions may be enhanced by targeting their presumed causal factors. An emotion-oriented variant of cognitive behavioral therapy for delusions (CBTd-E), designed to target affect regulation and maladaptive schemata, was evaluated for its effect on delusions. A single-blind, multicenter, randomized, waitlist-controlled trial was conducted in three German outpatient clinics. Ninety-four patients with psychotic disorders and persistent delusions were randomized to 25 individual sessions of CBTd-E over 6 months (n = 47) or waitlist (n = 47). CBTd-E included two modules designed to improve affect regulation and maladaptive schemata. Assessments were performed at baseline (T1), three months (T2), and six months (T3). Regression-based analysis of covariance at T3 in the intent-to-treat sample indicated no significant benefit for the CBT-E group in the primary outcome (Psychotic Symptom Rating Scale delusions subscale, d = -0.45 [CI: 0.36; -1.26]). Regarding secondary outcomes, a significant effect favoring CBTd-E was observed in general psychopathology (d = -0.56), but no effects on positive and negative symptoms, depression, general and social functioning, or antipsychotic dosage. Regarding the proposed target mechanisms, we found improved cognitive reappraisal (d = 0.59), worrying (d = -0.52), quality of sleep (d = -0.49), and self-esteem (d = 0.36). Despite its effect on the suggested target mechanisms, affect regulation and maladaptive schemata, and on general psychopathology, this emotion-focused variant of CBT did not show an effect on delusions. A possible avenue to achieve stronger effects on delusions is to personalize the modularized interventions.Trial registration: Clinicaltrials.gov Identifier: NCT02787135.