OBJECTIVES: Pregabalin, duloxetine, and milnacipran are the only pharmacological agents approved by the US FDA to treat fibromyalgia. However, amitriptyline, one of the oldest and cheapest drug, is an established off-label standard for the treatment of fibromyalgia. This study investigated the comparative effectiveness and acceptability of amitriptyline and FDA-approved drugs for fibromyalgia. METHODS: Bayesian network meta-analysis was performed in accordance with PRISMA guidelines. Electronic and manual searches were performed from PubMed, Embase, Cochrane, and Clinicaltrials.gov until November 20, 2018. The inclusion criteria were: 1) randomized, placebo-controlled trial on adult patients with fibromyalgia using amitriptyline or FDA approved drugs; 2) Reporting pain, sleep, depression, fatigue, health-related quality of life (QoL), or acceptability outcomes; and 3) minimum follow-up period of 4 weeks. Effect sizes reported as standardized mean differences (SMDs) for continuous outcomes, and odds ratios (ORs) for the acceptability outcome with 95% credible intervals (95% CrIs). RESULTS: 36 trials enrolling 11,930 patients were included. The mean age was 48.4 (SD 10.4) years; 11,262 (94.4%) were women. Compared with placebo, amitriptyline was associated with reduced sleep disturbances (SMD, –0.97; 95% CrI, –1.10 to –0.83), less fatigue (SMD, –0.64; 95% CrI, –0.75 to –0.53), and improved QoL (SMD, –0.8; 95% CrI, –0.94 to –0.65). Duloxetine 120mg was associated with the highest improvement in pain (SMD, –0.33; 95% CrI, –0.36 to –0.30) and depression (SMD, –0.25; 95% CrI, –0.32 to –0.17) versus placebo. All treatments were associated with inferior acceptability than placebo, except amitriptyline (OR, 0.78; 95% CrI, 0.31 to 1.66). Based on SUCRA, duloxetine 120mg might be the most effective for treating pain and depression, while amitriptyline might be the most acceptable and most effective for improving sleep, fatigue, and QoL. CONCLUSIONS: This NMA emphasizes the need for treatments to be tailored to individual symptoms, weighing the benefits and acceptability when prescribing medications to patients with fibromyalgia.