The efficacy of hot isostatic pressing (HIP) for enhancing fatigue performance is investigated for additively manufactured (AM) Ti-6Al-4V. The limitations of HIP are probed by varying the initial material state via the selection of AM system, powder chemical composition, and process parameters. We demonstrate that the fatigue performance of HIP’d AM Ti-6Al-4V depends on the as-built quality of the material. Differences in common material attributes, such as pre-HIP defect populations or post-HIP microstructure morphology, are shown to be insufficient to explain the observed discrepancies in performance. This implies that additional microstructure attributes or localized deviations from the expected structure control the failure of this material. Finally, HIP parameters outside ASTM recommendations were explored, where a reduced temperature and high-pressure treatment yielded significantly improved fatigue performance.