A 71-year-old Chinese male was referred for severe dry eyes who suffered from multiple corneal melting ulcers and underwent a long-term and high-dosage interferon alpha-2b (INFα-2b) treatment for multiple myeloma (MM). The patient was diagnosed to have MM 12 years ago, and since then INFα-2b (3-million units, intramuscularly, three times a week) was prescribed until the present. Two years ago, diffuse superficial punctuate epithelial defects, filaments and multiple melting ulcers in his cornea were noted. Sjögren's syndrome was diagnosed after the salivary gland biopsy. In addition to preservative-free topical lubricants, bilateral permanent punctal occlusion and tarsorraphy were performed but in vain. Topical and systemic immunosuppressants including corticosteroids, cyclosporin and methotrexate improved his corneal condition successfully. The present case suggests a relationship between INFα-2b and Sjögren's syndrome. Long-term use of INFα-2b may impair tear functions and complicate corneal melting ulcers. Immunosuppressants play a role in treatment of INFα-2b associated keratopathy.