<p>Erythromelalgia (EM) is a rare condition characterized by episodic erythema, warmth, and pain, typically at the extremities. Despite known associations with myeloproliferative and autoimmune disorders, comprehensive analysis of comorbidities has been limited by EM’s rarity. This study aims to identify significant comorbid associations to improve recognition and understanding of this challenging condition. We conducted a retrospective cohort study using the TriNetX research network, identifying 7,145 patients diagnosed with EM from February 2005 to February 2025. We evaluated associations between EM and selected myeloproliferative disorders, autoimmune conditions, mental health disorders, and metabolic conditions using odds ratios with 95% confidence intervals. The study cohort was predominantly female (73.15%) and white (78.93%). EM showed strongest associations with polycythemia vera (OR 27.05, 95% CI 14.37–50.92), essential thrombocythemia (OR 10.94, 95% CI 7.19–16.64), and Raynaud’s phenomenon (OR 17.28, 95% CI 13.20-22.65). Significant associations were also found with polyneuropathy (OR 6.76, 95% CI 5.91–7.74), systemic lupus erythematosus (OR 5.36, 95% CI 3.78–7.59), systemic sclerosis (OR 4.68, 95% CI 2.52–8.34), and mental health disorders including recurrent major depressive disorder (OR 1.41, 95% CI 1.24–1.61) and suicidal ideation (OR 1.48, 95% CI 1.08–2.05). Type I diabetes showed a positive but non-significant association (OR 1.31, 95% CI 1.00-1.73). This large-scale analysis confirms and quantifies EM’s strong associations with myeloproliferative and autoimmune conditions, while revealing unexpected negative correlations with several metabolic disorders. The significant association with mental health conditions underscores the impact of EM on quality of life. These findings may improve clinical recognition and guide future investigations into EM’s pathophysiology.</p>