OBJECTIVES: No head-to-head comparisons of droxidopa and midodrine for neurogenic orthostatic hypotension (nOH) have been conducted. nOH is due to underlying neurologic disorders and is characterized by ≥20 mm Hg decrease in systolic blood pressure (sBP) or ≥10 mm Hg decrease in diastolic BP within 3 minutes of standing. This research was conducted to provide a systematic indirect comparison of droxidopa and midodrine. METHODS: A mixed treatment comparison (MTC) was conducted using a Bayesian hierarchical model allowing for indirect comparison of the interventions. Randomized controlled trials (RCTs) for analysis inclusion were identified using a systematic literature review. RCTs were assessed for comparability based on patient population and outcome measures. Improvement in standing sBP was the efficacy outcome measured for this analysis. Supine hypertension risk was assessed as a commonly reported measure of safety. RESULTS: The network of 6 RCTs were included; 12 treatment arms across studies facilitated the indirect comparison of midodrine and droxidopa. There was reasonable agreement between number of unconstrained data points, residual deviance and pair-wise results, suggesting a coherent network. The fixed-effect 95% credibility intervals for sBP improvement (mm Hg) from baseline relative to placebo were (11.35, 22.95) for midodrine and (1.61, 8.90) for droxidopa, respectively (positive numbers indicate improvement over placebo). MTC estimates of 95% credibility levels for supine hypertension risk ratio (relative to placebo) were (1.2, 20) for midodrine and (0.72, 2.7) for droxidopa. Due to limitations of the clinical data, potential confounding factors (eg, gender and formulation differences) were not accounted for in examining treatment effects. CONCLUSIONS: Droxidopa and midodrine were both more effective versus placebo in increasing sBP, with a larger effect observed with midodrine treatment. However, midodrine was also associated with significantly greater risk of supine hypertension compared with placebo, while no statistically significant increased risk was observed with droxidopa.