Pharmacogenetic markers are current targets for the personalized treatment of psychosis. Limited data exist on COMT and NRG1 polymorphisms in relation to risperidone treatment. This study focuses on the impact of COMT rs4680 and NRG1 (rs35753505, rs3924999) polymorphisms on risperidone treatment in schizophrenia spectrum disorders (SSDs). This study included 103 subjects with SSD treated with risperidone monotherapy. COMT rs4680, NRG1 rs35753505, and rs3924999 were analyzed by RT-PCR. Participants were evaluated via the Positive and Negative Syndrome Scale (PANSS) after six weeks. Socio-demographic and clinical characteristics were collected. COMT rs4680 genotypes significantly differed in PANSS N scores at admission: AG>AA genotypes ( = 0.03). After six weeks of risperidone, PANSS G improvement was AA>GG ( = 0.05). The PANSS total score was as follows: AA>AG ( = 0.04), AA>GG ( = 0.02). NRG1 rs35753504 genotypes significantly differed across educational levels, with CC>CT ( = 0.02), and regarding the number of episodes, TT>CC, CT>CC ( = 0.01). The PANSS total score after six weeks of treatment showed a better improvement for TT<CT genotypes ( = 0.01). NRG1 rs3924999 genotypes revealed GG<AG ( = 0.02) for PANSS G scores after six weeks, with AG and GG requiring higher doses ( = 0.007, = 0.02). Overall, our study suggests that the genetic polymorphisms COMT rs4680, NRG1 rs35753505, and rs3924999 significantly impact the treatment response to risperidone in patients with SSD.