Hairy cell leukemia variant (HCLv), described 30 years ago, was reported to present with high disease burden and less often leukopenia, and later was reported to be resistant to purine analogs. Patients with HCLv were overrepresented among patients with HCL seeking relapsed/refractory trials. To compare clinical and molecular features of classic HCL (HCLc) and HCLv, 85 rearrangements expressing immunoglobulin variable heavy chain were sequenced, taken from 20 patients with HCLv and 62 with HCLc. The gene VH4-34, commonly used in autoimmune disorders, was found in eight patients (40%) with HCLv versus six (10%) with HCLc (p = 0.004). Ninety-three percent of the VH4-34 rearrangements were unmutated, defined as >98% homologous to the germline sequence. Clinical features of VH4-34+ patients that were similar to those with HCLv included higher white blood cell counts at diagnosis (p = 0.002) and lower response (p = 0.00001) and progression-free survival (p = 0.007) after first-line cladribine, and shorter overall survival from diagnosis (p < 0.0001). It was found that VH4-34 was independent from HCLv and a stronger predictor than HCLv in associating with poor prognosis. We conclude that VH4-34+ hairy cell leukemia, which only partly overlaps with HCLv, is associated with poor prognosis after single-agent cladribine. However, cases are observed which respond well to antibody therapy either alone or in combination with purine analog.