Objectives The aim of this study was to compare outcomes of major lower limb amputation (MLA) in patients with and without cancer and with cancer patients receiving palliation over amputation for their unsalvageable limb. Methods Cancer patients who underwent a major amputation or palliation between 2013 and 2018 were included. Comparison groups were cancer-MLA (active/managed cancers), non-cancer MLA (historic cancer or no cancer history) and cancer-palliation at presentation with unsalvageable limbs. Prospectively collected data was retrospectively analysed for outcomes including survival, postoperative complications, length of stay, suitability for rehabilitation and discharge destination. Results 262 (cancer and non-cancer) patients underwent MLA and 18 patients with cancer received palliation. Of those amputated, 26 (9.9%) had active or managed cancer, of which 12 were diagnosed in the 6 months before MLA. Cancer-MLA patients presented with more acute ischaemia compared to non-cancer patients. Median survival was significantly different between the cancer-MLA (14.1 [9.5 - 29.5, 95% CI] months), non-cancer MLA (57.7 [45 - 73.6, 95% CI] months) and cancer-palliation (.6 [.4 - 2.3, 95% CI] months) groups, P < .001. A significantly higher proportion of cancer-MLA patients (10/26, 38.5%) were deemed unsuitable for rehabilitation in post-operative assessment compared to non-cancer MLA (21/236, 8.9%) patients, P < .001. There was a variation in destinations of discharge, with a greater proportion of cancer-MLA patients (4/26, 15.4%) going to a nursing home compared to non-cancer MLA (10/236, 4.2%) patients, P = .016. Conclusion Cancer is prevalent among vascular amputees, with a large proportion being occult diagnoses. Cancer is associated with poorer outcomes following amputation, but survival remains significantly better compared to palliation in cancer patients presenting with unsalvageable limbs.