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Background: A pathogenic link between hepatitis C virus (HCV) and MALT-type lymphomas has been suggested. However, studies assessing the role of HCV infection separately in different forms of MALT lymphomas are not available. Patients and methods: The prevalence and clinical implications of HCV seropositivity were analyzed in 55 patients with ocular adnexa lymphoma (OAL) of MALT-type. Results: HCV seropositivity was detected in seven (13%) patients. At presentation, HCV infection was significantly associated with concomitant extra-orbital disease, lymph node dissemination and involvement of additional extranodal organs. HCV seropositivity was associated also with a higher relapse rate and worse progression-free survival. In fact, 16 patients experienced relapse after first-line treatment: five (71%) were HCV-seropositive and 11 (23%) were HCV-seronegative, with a median TTP of 31 and 50+ months (P = 0.01), and a 5-year progression-free survival of 43 +/- 18% and 77 +/- 7% (P = 0.005), respectively. HCV-seropositive patients experienced frequent relapses despite further lines of therapy; relapses were systemic in all cases but one; multiple subcutaneous nodules were common at relapse. Conclusions: HCV seropositivity is present in 13% of OAL of MALT-type. Concomitant HCV infection is associated with more disseminated disease and aggressive behavior in OAL, with a consequent potential negative impact in patients managed with radiotherapy alone.