We present a case of metastatic spreading to the testicle in a 46-year-old patient with renal cell carcinoma, "clear-cell" type, during interleukin-2 combined subcutaneous plus aerosol treatment. Testicular metastasis occurred while the patient showed a response to the treatment with disappearance of lung lesions and reduction of lymph-nodes lesions. After orchiectomy with spermatic cord resection and disease re-evaluation confirming the previous response, the patient re-started immunotherapy. The contrast between systemic disease response to treatment and disease testicular progression might be explained by a relative insensitivity of the testicle to interleukin-2 immunotherapy as a result of a possible establishment of an immunosuppressive microenvironment. We believe that the rarity of this metastatic site and the intriguing possible mechanisms at its base, makes an interesting case for clinicians.