Background: Research on cognitive functions in treatment-resistant schizophrenia (TRS) has focused on chronic patients, complicating the distinction between disease-related deficits from those influenced by chronicity or antipsychotic exposure. Identifying early cognitive differences could offer insights into the nature of TRS cognitive performance and serve as potential markers of treatment resistance. Methods: Cohort study of 81 first-episode schizophrenia patients from Chile. Patients were followed-up and classified as TRS if they met TRRIP criteria or were prescribed clozapine at any point. 57 healthy controls were recruited for group comparisons. Cognitive performance was assessed using the MATRICS Consensus Cognitive Battery. Results: 51 patients were allocated to the treatment-responsive group (TRESP) and 30 to the TRS sample. Multivariable analyses controlling for age and sex revealed a worse TRS performance in processing speed, verbal fluency, attention/vigilance and working memory (p values <0.05). After multiple comparison corrections, only speed of processing remained significant. When accounting for symptom severity, antipsychotic dose and duration of untreated psychosis (DUP), TRS subjects still showed significantly lower processing speed (BACS, p = 0.036; TMT-A, p = 0.027), which was not significant after correcting for multiple comparisons. Discussion: TRS patients show slower processing speed compared to TRESP already during first episode, that is not entirely driven by symptom severity, antipsychotic dose and DUP. Processing speed emerges as an early deficit that could aid in the timely identification of patients on a treatment resistance trajectory and facilitate the prompt implementation of treatments such as clozapine.