The block Ti-6Al-4V alloy was fabricated by selective laser melting (SLM) and then subjected to hot isostatic pressing (HIP) treatment. Next, the influence of HIP on the high cycle fatigue performance of the alloy with notch (stress concentration factor K_t = 3) was assessed, while elucidating the mechanisms related with the high notch sensitivity of the SLM+HIP Ti-6Al-4V alloy. The results indicate that although the SLM+HIP Ti-6Al-4V alloy exhibits superior static tensile strength and hardness compared to wrought counterparts, its fatigue performance under notched conditions is significantly compromised, with the fatigue limit decreasing from 250 MPa (wrought) to 150 MPa. Further analysis reveals that the high notch sensitivity of the SLM+HIP Ti-6Al-4V alloy may mainly be attributed to two factors: (1) differences in crack initiation mechanisms, i.e., as the crack initiation region of SLM+HIP alloy exhibits cleavage-like brittle fracture morphology, distinctly different from the ductile fracture morphology of the forged alloy, leading to a higher propensity for brittle crack initiation; and (2) the influence of grain size characteristics, namely the SLM+HIP alloy exhibits a unique lath-like grain structure, with an overall larger grain size compared to the forged alloy. Specifically, the average grain size in the X and Z directions is 2.34 and 2.58 μm, respectively, which is significantly larger than 1.63 μm in the forged alloy. This increased grain size exacerbates its notch sensitivity, making cracks more prone to initiation and propagation during the fatigue process.