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Aim: Current treatments for obsessive-compulsive disorder (OCD) encounter resistance and limiting adverse events, necessitating novel therapeutic strategies. This study aimed to investigate the benefits of naproxen, a medication with effects on inflammation and neuronal function, on OCD., Methods: One hundred and four OCD outpatients with a Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) score of >21 were equally assigned to receive fluoxetine plus either naproxen 250 mg or matched placebo q12hr. Patients were assessed using the Y-BOCS by recording the subscale scores at baseline and weeks 5 and 10 to evaluate efficacy. They were also assessed in terms of tolerability., Results: Data from 96 patients were analyzed. The baseline characteristics were comparable between the groups. There were significant time-treatment interaction effects on the obsession subscale ( η P 2  = 0.055) and total ( η P 2  = 0.043) scores of Y-BOCS. Reductions in the obsession subscale and total scores of Y-BOCS were significantly greater in the fluoxetine plus naproxen group until the endpoint (Cohen's d = 0.560 and Cohen's d = 0.477, respectively). However, the difference in compulsion subscale score changes between the groups was not significant. Respondents with a reduction of ≥35% in Y-BOCS total scores were significantly more in the fluoxetine plus naproxen group (80.0% versus 47.8%). The side effect frequencies were comparable between the groups., Conclusion: Naproxen, adjunct to fluoxetine, outperformed adjunctive placebo in treating obsession and total symptoms of OCD patients in a safe and tolerable manner., Clinical Trial Registration: The study protocol was registered and published in the Iranian Registry of Clinical Trials (http://www.irct.ir; registration number IRCT20090117001556N139)., (© 2024 The Author(s). Psychiatry and Clinical Neurosciences © 2024 Japanese Society of Psychiatry and Neurology.)