Progressive multisystemic disease caused by Blastomyces dermatitidis was diagnosed in a 17-year-old Quarter horse broodmare. The mare had been treated unsuccessfully with antibiotics for mastitis 3 months postpartum. The disease progressed to exudative cutaneous lesions affecting the ventrum, pectoral region, and limbs accompanied by weight loss across several months. Yeast bodies were observed in swabs of the cutaneous exudate, suggesting a clinical diagnosis of blastomycosis. Following referral, pleural effusion, cavitated lung lesions, and hyperproteinemia were identified, and the mare was euthanized because of poor prognosis. Necropsy revealed extensive pyogranulomas in the mammary gland, skin, subcutaneous tissues, and lungs, accompanied by thrombi in major blood vessels of the lungs and hind limbs. Histologically, pyogranulomatous inflammation was evident in many tissues, and fungal organisms were seen in sections of mammary gland, skin, subcutis, pericardium, and lung. Blastomyces dermatitidis was cultured from mammary tissue, lungs, lymph node, and an inguinal abscess. Although blastomycosis is endemic in the area of origin of the mare in northwestern Wisconsin, the disease is extremely rare in horses and hence easily misdiagnosed. Unique features of this case included the extent of mammary gland involvement and the presence of thrombi in multiple sites.