There are no identified biomarkers that could predict response to antiangiogenic or traditional chemoimmunotherapy in metastatic melanoma. We hypothesized that soluble angiogenic factor receptors might help us to identify patients responsive to treatment. A series of 48 patients with stage IV melanoma participating in two phase II clinical trials were included. The trials included treatment with carboplatin, vinorelbine, and subcutaneous interleukin-2 (n=22) or treatment with bevacizumab, dacarbazine, and low-dose interferon-α2a (n=26).Serum samples were prospectively collected and soluble vascular endothelial growth factor receptor 1 (s-VEGFR-1) and 2 (s-VEGFR-2) were measured before starting the trial treatment and during response evaluation.There was a trend toward longer overall survival among patients with higher-than-median serum VEGFR-1 levels (21.3 months) compared with 12.3 months in patients with low pretreatment s-VEGFR-1 levels (P=0.146). Pretreatment s-VEGFR-2 levels did not correlate to survival. Serum VEGFR-2 levels decreased during therapy in 44% of the patients and increased in 56% of the patients. VEGFR-2 increased in 78% (14 of 18) of the patients who progressed during therapy (P=0.017). VEGFR-2 decrease was associated with clinical benefit in 65% of the patients (11 of 17) and with progression in only four patients (P=0.016).High pretreatment levels of s-VEGFR-1 are associated with improved prognosis among patients with metastatic melanoma independently on therapy, whereas increased VEGFR-2 levels during therapy are associated with disease progression. These markers might be useful in selecting patients responsive to antiangiogenic therapy.