Human leukocyte antigen (HLA) class I plays an important role in tumor recognition and rejection. Total or selective losses of HLA class I antigens (classified into seven HLA class I altered phenotypes) represent one of the main routes of tumor escape from immune surveillance. Abnormal expression of HLA class I has been reported in different human tumor samples with distinct underlying mechanisms. Notably, different molecular mechanisms can generate the same altered HLA class I phenotype. Here, we describe various molecular mechanisms that can lead to HLA total loss or downregulation (phenotype I) in melanoma, colorectal carcinoma and bladder cancer.