Several brain- and blood-based gene expression studies in patients with psychotic disorders (e.g., schizophrenia) have identified genes in the ubiquitin proteasome system (UPS) pathway as putative biomarkers. However, to date an examination of the UPS pathway in the broader context of symptom severity in psychosis has not been conducted. The purpose of this study was to investigate the correlation between clinical scores on the Scales for the Assessment of Positive and Negative Symptoms (SAPS–SANS) and expression of 43 highly annotated genes within the UPS pathway in blood from patients with psychosis. A sample of 19 psychotic patients diagnosed with schizophrenia (n = 13) or bipolar disorder (n = 6) were recruited. Pearson's partial correlations, adjusting for gender, ethnicity, age, education, medication, smoking, and past 6-month substance use, were performed between each of the selected UPS genes and both scales. Significant Bonferroni-adjusted positive associations were observed between SAPS scores and two ubiquitin conjugation genes (i.e., UBE2K, SIAH2), while a negative association was observed with one deubiquitination gene (i.e., USP2). No gene expression levels were significantly associated with scores on the SANS after correction for multiple testing. Our findings suggest that dysregulation of the UPS, specifically ubiquitin conjugation and deubiquitination, may point to a possible underlying biological mechanism for severity of positive but not negative symptoms.