Our aim was to analyze the association of HSPA1B genotypes and treatment response measured by the changes of psychopathology and neurocognitive symptoms in patients with first-episode psychosis (FEP) after 18 months of treatment. A sample of 159 patients with FEP admitted at two Croatian psychiatric hospitals in the period between year 2014 and year 2017 was assessed at baseline and after 18 months of follow-up with Positive and Negative Syndrome Scale (PANSS), Calgary Depression Scale for Schizophrenia (CDSS) and a battery of neurocognitive tests. Associations of scale and test results with HSPA1B polymorphic locus rs1061581 were analyzed using the general linear model. The carriers of the AA genotype showed the highest improvement in CDSS and RAVLT A test after the 18-month follow-up. Concordantly, we found significantly higher improvement assessed with the CDSS, RAVLT A, RAVLT A 30' and positive PANSS scales in the not-GG (AA/AG) group compared with the GG group. Our study suggests that HSPA1B rs1061581variants may moderate treatment response in FEP measured with changes of psychopathology and neurocognitive test results.