Abstract Continuous prostanoid infusions are recommended for patients with advanced pulmonary arterial hypertension. Infusion site pain has discouraged some physicians from considering subcutaneous (SQ) treprostinil therapy even though it has safety and convenience advantages over intravenous epoprostenol. We conducted a 1-year prospective study of patients utilizing SQ treprostinil. We provided counseling on infrequent site changes and a written analgesic protocol including narcotics. After placement of a new site, subjects recorded daily pain scores and analgesic use. Twenty-six of 29 patients consented, including 4 patients who had recently started therapy. They returned 203 diaries, and we captured every site change in a diary. Sixteen subjects returned 8 or fewer diaries during 12 months, and 20% of diaries documented only mild discomfort. The majority of diaries documented brief periods of severe pain, but this had generally abated by day 7. Contrary to published guidelines, infusion site pain was independent of treprostinil dose in a rigorous analysis. There were 3 significant local reactions but no systemic illness. No subject discontinued SQ treprostinil because of site discomfort. Subjects reported satisfaction with their treatment using a validated assessment, and quality-of-life scores were favorable. A strategy emphasizing infrequent site changes and early analgesia can facilitate use of SQ treprostinil. These data may allow physicians to consider treprostinil earlier in the treatment algorithm for this fatal disease.