19003 Background: Most clinical trials with adjuvant therapy in melanoma concentrate on high-risk patients including those with metastases to regional lymph nodes (LN), stage III and locally advanced T4, i.e., stage IIB and IIC. These trials may be missing the advantageous results in the relatively earlier stages. Methods: We reviewed the new American Joint Committee on Cancer (AJCC) for cancer staging of cutaneous melanoma and Balchs’ data for the prognostic factors. The data was correlated to patients’ survival expressed by the natural history of the disease. Results: We grouped the reported survival data into 3 risk groups, excluding patients with distant metastases. Group 1: 2–4mm deep primary with ulceration, >4mm deep primary without ulceration, micrometastases to 1–3 LN, primary not ulcerated; Group 2: >4mm deep primary with ulceration, micrometastases to 1–3 LN ulcerated primary, macrometastases to 1–3 LN, primary not ulcerated intransit metastases/satellitosis, without LN metastases; Group 3: macrometastases to 1–3 LN, ulcerated primary, metastases to 4 or more LN, matted LN, and/or intransit, metastases/satellitosis with LN metastases. The table summarizes the results. Conclusions: 1. Over one-third of the patients in group 1 died of disease in the first 5 years. They should be considered at intermediate risk and should receive adjuvant therapy. 2. Patient prognosis should determine the intensity of target therapy utilized in the adjuvant arena. While anti-CTLA-4 may be sufficient for group 1, the addition of anti-kinases may be required in group 2 and more so in group 3. [Table: see text] No significant financial relationships to disclose.