Background: Biomarkers of immune dysfunction, such as serum inflammatory cytokines, may provide clues to pathophysiology in persons presenting with first-episode psychosis (FEP). Aim: Investigate the expression of serum inflammatory cytokines in FEP. Methods: In this sub-study of an ongoing longitudinal HIV in FEP study, blood samples were collected from February 2021 to January 2023 in participants meeting DSM-5 criteria for FEP who were aged 18 to 45 years and had less than six weeks of antipsychotic treatment. A multiplex ELISA assay measured interleukin (IL) 6, 8 and 10 levels, correlating them with socio-demographic factors, body mass index (BMI), psychosis severity (PANSS), depression (PHQ-9), cognitive screening (International HIV Dementia Scale), substance use (WHO ASSIST) and HIV status. Results: 70 participants were included (male =74%), with substance use being present in 79-83%, and 63% reported exposure to trauma during childhood. Current alcohol use was associated with elevated IL-8 levels (p=0.01), and high IL-10 levels correlated with lifetime and current alcohol use (p=0.02, p=0.04, respectively). Sensitivity analysis of 58 HIV-negative patients found associations between elevated IL-6 and IL-8 levels and current alcohol use (p=0.04, p=0.01), and elevated IL-10 levels with lifetime tobacco use (p=0.01) and lifetime and current alcohol use (p=0.00, p=0.03). Cytokines were not significantly associated with psychosis and neurocognitive performance. Conclusion: While there is evidence of immune dysfunction in FEP, there is no clear clinical significance of this dysfunction. Better methodologically designed studies could assist in understanding the significance of immune dysfunction.