Paraneoplastic syndromes are an uncommon, yet well-described, phenomenon in cancer patients. The syndrome of granulocytosis caused by granulocyte colony-stimulating factor (G-CSF) production by tumors is rare and is difficult to diagnose in patients receiving treatment for metastatic disease. From January 2005 to May 2009, 626 patients were evaluated for treatment of metastatic melanoma. At initial evaluation or during the course of treatment, six patients had an elevated white blood cell count and no evidence of infection. All six had significantly elevated serum G-CSF. The level of serum G-CSF was directly correlated with the absolute neutrophil count. In-vitro assay of melanoma tumor from two patients showed elevated G-CSF in cell culture supernatant. The paraneoplastic syndrome of granulocytosis resulting from ectopic G-CSF production in patients with metastatic melanoma is rare. This diagnosis should be considered when common causes of granulocytosis have been ruled out.