Introduction: There is evidence that early intervention contributes to improving the prognosis and course of first-episode psychosis (FEP). However, further randomised treatment clinical trials are needed. Objectives: The aim of this study was to compare the efficacy of a combined clinical treatment involving Cognitive Behavioural Therapy (CBT) as an adjunctive to treatment-as-usual (TAU) (CBT+TAU) versus TAU alone for FEP. Patients and methods: In this multicentre, single-blind, randomised controlled trial, 177 participants were randomly allocated to either CBT+TAU or TAU. The primary outcome was post-treatment patient functioning. Results: The CBT+TAU group showed a greater improvement in functioning, which was measured using the Global Assessment Functioning (GAF) and Functioning Assessment Short Test (FAST), compared to the TAU group post-treatment. The CBT+TAU participants exhibited a greater decline in depressive, negative, and general psychotic symptoms; a better awareness of the disease and treatment adherence; and a greater increase in brain-derived neurotrophic factor levels than TAU participants. Conclusions: Early intervention based on a combined clinical treatment involving CBT as an adjunctive to standard treatment may improve clinical and functional outcomes in FEP.