Background: It has been suggested that spinal manipulation may alter sensorimotor integration in the central nervous system and therefore may be used to treat central sensitization syndromes. Objective: To investigate the effectiveness of spinal manipulation in addition to pharmacological treatment in patients with fibromyalgia. Design: A single-center, randomized, and placebo-controlled trial with three parallel arms SETTING: Outpatient clinics at a tertiary health care facility. Participants: Female patients aged 18-55 years receiving pharmacological treatment. Interventions: Spinal manipulation, sham manipulation, and control groups. Patients in the spinal manipulation group received high-velocity low-amplitude manipulation treatment twice a week for 3 weeks. Patients in the sham group received an application that was very similar to the active treatment but was not expected to have any real therapeutic effect. Patients in the control group continued to receive pharmacological therapy. Main outcome measures: The primary outcome, pain score (visual analog scale), and secondary outcomes, pressure pain threshold (PPT), Revised Fibromyalgia Impact Questionnaire (FIQR), Widespread Pain Index (WPI), and Fibromyalgia Severity Score (FSS) were measured before, 1 month, and 3 months after randomization. Results: Sixty patients with a mean age of 41.7 years (SD = 8.0) were enrolled in the study. A mixed-design repeated analysis of covariance was used to test the data. At 1 month after randomization, pain scores did not differ between groups. At 3 months after randomization, the spinal manipulation group had a significantly lower pain score (adjusted mean = 4.3 cm, SE: 0.4) than the control group (adjusted mean = 6.8 cm, SE: 0.4) and the sham manipulation group (adjusted mean = 5.7 cm, SE: 0.4). PPT did not differ between groups at any time point. FIQR, WPI, and FSS showed some improvement 1 or 3 months after randomization in favor of the spinal manipulation group. Conclusions: Spinal manipulation used in addition to pharmacological treatment in young/middle-aged female patients with fibromyalgia could be an effective treatment for pain, disease severity, and functionality.