Abstract Title Hypertensive Crisis Unresponsive to Standard Therapy: The Interplay of Pulmonary Hypertension and Scleroderma Renal Crisis in Systemic Sclerosis Background Systemic sclerosis (SSc) is a complex autoimmune disease that can affect nearly every organ system, often leading to serious and sometimes life-threatening complications. Among its most challenging manifestations are pulmonary hypertension (PH) and scleroderma renal crisis (SRC), both of which can dramatically impact patient outcomes. This case report describes a 54-year-old African American woman with a 12-year history of SSc who developed refractory hypertension, right heart failure due to PH, and SRC. Despite aggressive antihypertensive therapy (on seven drugs), her blood pressure remained uncontrolled, highlighting the complexities of managing overlapping pathologies. Case Presentation A 54-year-old African American woman with a 12-year history of systemic sclerosis presented with progressive dyspnea, fatigue, and new-onset lower extremity edema. Diagnostic workup confirmed pulmonary arterial hypertension (PAH) through right heart catheterization and revealed right ventricular dysfunction on echocardiography. Concurrently, she developed acute kidney injury with a serum creatinine of 3.5 mg/dL and malignant hypertension, consistent with scleroderma renal crisis (SRC). Despite an intensive antihypertensive regimen that included amlodipine, carvedilol, spironolactone, hydrochlorothiazide, clonidine patch, hydralazine, and losartan, her blood pressure remained uncontrolled, averaging 170/105 mmHg. ACE inhibitors, typically the cornerstone treatment for SRC, were contraindicated due to an allergy. Intravenous prostacyclin therapy was initiated to manage her PAH, but her renal function continued to decline, prompting consideration for renal replacement therapy. Discussion Scleroderma renal crisis, characterized by malignant hypertension and rapid renal deterioration, is a life-threatening complication of SSc. The coexistence of pulmonary hypertension adds another layer of complexity, as therapies for PH may interact with anti-hypertensive agents. Refractory hypertension in this context is driven by endothelial dysfunction and vasculopathy, limiting the efficacy of conventional treatments. Targeted therapies, such as endothelin receptor antagonists and prostacyclin analogs, may offer additional benefits but require careful consideration. This case highlights the critical need for a multidisciplinary approach, involving rheumatology, cardiology, nephrology, and often pulmonology. Close collaboration ensures that care is tailored and responsive to the patient’s dynamic needs. Such complex scenarios remind us of the importance of tailored, patient-focused care and ongoing innovation in the management of systemic sclerosis and its complications. Future research should focus on developing novel therapeutic strategies to address the unique pathophysiology of these intertwined conditions.