The catechol-O-methyltransferase (COMT) gene is thought to have an important role in the etiopathogenesis of schizophrenia, but there are conflicting results regarding its role in clinical presentation. We aimed to elucidate the relationship between the single nucleotide polymorphisms (SNPs) in the COMT gene and the severity of positive and negative symptoms. In order to investigate the relationship, the PubMed, PubMed Central, Scopus, and Cochrane CENTRAL databases were screened for eligible articles. Thirty-eight studies, including 4443 adult patients with schizophrenia, were included in the quantitative analyses, and four studies were qualitatively assessed. Quantitative analyses were performed for acutely ill and clinically stable patient subgroups regarding the different genotypes of rs4680 SNP. Our results showed that the severity of negative symptoms was higher in patients who were rs4680 Met homozygous compared to Val/Met heterozygotes only in acutely ill samples. There was no other significant difference between genotypes. Meta-regression did not reveal any significant moderator effect on the difference in negative symptoms. General psychopathology, positive, negative, and total psychotic symptom levels also were similar between Val homozygotes and Met carriers. Nonetheless, there are some limitations in the study. First, SNPs except for rs4680 were under-researched because of the limited number of studies. Second, high heterogeneity across studies was the main concern. Our results suggested that the COMT rs4680 Met allele was associated with higher levels of negative symptoms within acutely ill patients. Future studies should focus on specific patient subgroups to reveal the moderating effects of SNPs.