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Aim: The aim of this study was to explore the effectiveness and safety of pentoxifylline as an adjuvant to risperidone in mitigating the negative symptoms in patients with chronic schizophrenia. Methods: In this randomized, placebo‐controlled study, eighty outpatients with chronic schizophrenia were given risperidone for 8 weeks along with either pentoxifylline or a placebo. The positive and negative syndrome scale (PANSS) was used to assess patients at the start of the trial, as well as at 2, 4, 6, and 8 weeks. Pre‐ and posttreatment serum levels of cAMP, TNF‐α‐, and IL‐6 were measured. Results: The pentoxifylline group revealed a significant effect for time‐treatment interaction on PANSS‐negative subscale scores (p < 0.001), PANSS general psychopathology subscale scores (p < 0.001), and PANSS total scores (p < 0.001), but not on PANSS‐positive subscale scores (p = 0.169). Additionally, when compared to the placebo group, the pentoxifylline group demonstrated a statistically significant increase in cAMP serum level and a statistically significant decrease in TNF‐α and IL‐6 serum levels. Conclusion: Pentoxifylline adjunctive therapy with risperidone for 8 weeks was found to be promising in mitigating the negative symptoms in patients with chronic schizophrenia. Trial registration number: NCT04094207. [ABSTRACT FROM AUTHOR]