Objective: Fibromyalgia (FM) is a debilitating chronic pain condition with few treatment options. Central sensitization and neuroinflammation have been forwarded as models of FM pathophysiology, both of which indicate dextromethorphan (DXM) as a potential treatment. DXM is an NMDA-receptor antagonist and microglial modulator with anti-neuroinflammatory properties at low doses. It is available for clinical use but has not been tested as a treatment for FM at low dosages. This study evaluated the effectiveness of DXM in treating FM-associated symptoms. Methods: In a single-blind, placebo-controlled trial, 14 women meeting the 2010 American College of Rheumatology criteria for FM received a placebo for five weeks, followed by 20 mg DXM for ten weeks, while providing daily symptom reports on a 0–100 scale. Pain and physical activity were the primary and secondary outcomes, respectively. Daily symptom ratings during the last four weeks of placebo were contrasted with ratings during the last four weeks of the active treatment using generalized estimating equations (GEE). Results: DXM was well tolerated, and treatment adherence was high. Baseline pain was reduced by at least 20% in six participants. Self-reported daily pain and physical activity in the entire cohort were not significantly different between the placebo and DXM conditions, and the primary hypotheses were not supported. Exploratory analyses using the entire placebo and DXM data showed that pain was significantly lower in the DXM condition than in the placebo condition (b=−9.933, p=0.013). Discussion: A strong clinical effect of DXM was not observed at the 20mg/day dosage.