Two cats were admitted for skin lesions and lethargy. The first cat showed acute facial and limb crusting, pustular dermatitis, severe depression and poor appetite. The second cat showed crusting and hemorrhagic lesions on the nasal planum associated to anorexia and lethargy. EDTA blood and swab of cutaneous and mucosal ulceration were tested for feline calicivirus, feline herpesvirus and Chlamydia spp by RT-PCR. Both blood, skin and mucosal lesions were positive for FCV. Cats were negative for feline leukemia virus and feline immunodeficiency virus. Cytology of skin lesions was no consistent with pyoderma and pemphigus foliaceus. Blood analysis revealed hypereosinophilia and systemic inflammatory syndrome. Based on these finding, a diagnosis of systemic calicivirus was made. Both cats were treated with oral famciclovir. Thirty-nine days and Thirty-two days after starting antiviral therapy, cutaneous and mucosal lesions were completely healed in respectively the first and the second cat. No consensual treatment of calicivirus infection exists and systemic disease is often fatal. We report two cases of systemic calicivirus infection associated with skin lesions successfully treated with famciclovir, suggesting the antiviral effect of famciclovir against calicivirus.