Spondyloarthritis (SpA) is a group of inflammatory rheumatic diseases characterized by common clinical features, such as inflammatory enthesitis, arthritis and/or back pain. SpA is strongly associated with human leukocyte antigen (HLA) class I allotype B27. Ankylosing spondylitis has historically been the SpA subgroup with one of the strongest, best-proven associations with HLA-B27. The remaining SpA subgroups, namely psoriatic arthritis (PsA), inflammatory bowel diseases-associated arthritis/spondylitis, reactive arthritis, and undifferentiated SpA (uSpA), have also been associated with HLA allotypes other than HLA-B27. In this retrospective study, we analyzed the association between the HLA class I and II haplotypes and the susceptibility to enthesitis and/or arthritis (E/A). Special attention was paid to E/A responding to disease-modifying antirheumatic drugs (DMARDs) not fulfilling ASAS classification criteria (ASAS−), as compared to ASAS+ forms including PsA and uSpA. The whole E/A group showed significant independent associations with HLA-A28(68), B27, Cw3, Cw12, and DQ1; taken singly, PsA was associated with HLA-B27 and DQ1, uSpA with HLA-B16(38,39) and B27, and E/A ASAS− with HLA-A28(68), Cw8, and Cw12. This study identified novel risk HLA allotypes for different SpA subgroups in an Italian population. HLA typing could aid the diagnosis and treatment of E/A subgroups, including DMARDS-responsive forms not fulfilling ASAS classification criteria.