Background <p>Home parenteral nutrition (HPN) is indicated for patients with intestinal failure, but its use in cancer patients requires careful consideration due to the unique challenges and complexities involved.</p> Methods <p>This prospective cohort study analyzed data from cancer patients receiving HPN, recorded in the Canadian HPN Registry from 2003 to 2022. Patients were divided into two groups: those with gastrointestinal or gynecologic cancer and a propensity score-matched cohort of non-cancer patients. The objective was to assess survival rates by performance status and prescription decade in both groups. Secondary objectives were to compare complications between the groups.</p> Results <p>A total of 400 HPN patients were enrolled: 200 cancer patients (128 gastrointestinal, 72 gynecologic) and 200 matched non-cancer patients. Median age (interquartile range) was 58 (16) years for cancer and 56 (19) for non-cancer groups, with 71.5% and 66.5% female, respectively. Median survival was 1.71 years (95% confidence interval (CI), 0.81–2.61) for gastrointestinal cancer, 0.99 years (95% CI, 0.36–1.6) for gynecologic cancer, and 3.89 years (95% CI, 2.72–5.06) for non-cancer patients (<i>p</i>-value &lt; 0.001). Survival showed no improvement over two decades. Patients with Karnofsky Performance Scale (KPS) ≤ 50 had shorter survival. Catheter complications and HPN-related hospitalizations were similar, but HPN-related liver disease was more common in non-cancer patients (16.5% vs. 9%, <i>p</i>-value = 0.025).</p> Conclusion <p>Survival for patients with gastrointestinal and gynecologic cancer and co-existing intestinal failure has not improved over the past two decades, with poorer outcomes observed in those with low KPS. Complication rates were similar in both groups.</p> <p></p>