Subjects must be diagnosed with melanoma. All subjects receive sentinel lymphadenectomy. If the subject is sentinel node positive and meets study requirements, the subject is randomized to receive either (1) completion lymphadenectomy (2) observation with nodal ultrasound. Subjects are then followed for 10 years.

Inclusion Criteria:

1. Ability to provide informed consent.

2. Between 18 and 75 years of age.

3. Have a primary melanoma that is cutaneous (including head, neck, trunk, extremity, scalp, palm, sole, subungual skin tissues).

4. Have clear margins following WLE.

5. ECOG performance status 0-1.

6. Life expectancy of at least 10 years from the time of diagnosis, not considering the melanoma in question, as determined by the PI.

7. Willing to return to the MSLT-II center for follow up examinations and procedures as outlined in the protocol.

8. Randomization and/or CLND (as appropriate to randomization arm) must be completed no more than 120 days following the diagnostic biopsy of the primary melanoma.

9. Have a melanoma-related tumor-positive SN, determined by either of the following methods:

   1. Diagnosis of tumor-positive SN by MSLT-II center institutional pathologist by either H&E or IHC (using S-100, Mart-1, and HMB-45).

   2. Diagnosis of tumor-positive SN by RT-PCR analysis performed at JWCI, provided the primary melanoma fits into one of the following categories:

      • Breslow thickness of 1.20 mm or greater and Clark Level III
      • Clark Level IV or V, regardless of Breslow thickness
      • Ulceration, regardless of Breslow thickness or Clark level

Exclusion Criteria:

1. History of previous or concurrent (i.e., second primary) invasive melanoma.
2. Primary melanoma of the eye, ears, mucous membranes or internal viscera. (Primary of the skin of the external ear is acceptable.)
3. Physical, clinical, radiographic or pathologic evidence of satellite, in-transit, regional, or distant metastatic disease.
4. Any additional solid tumor or hematologic malignancy during the past 5 years except T1 skin lesions of squamous cell carcinoma, basal cell carcinoma, or uterine cervical cancer.
5. Skin grafts, tissue transfers or flaps that have the potential to alter the lymphatic drainage pattern from the primary melanoma to a LN basin.
6. Allergy to vital blue dye or any radiocolloid.
7. Inability to localize 1-2 SN drainage basins via LM (e.g., no basins found, more than 2 basins found, proximity of the primary melanoma to the regional draining basin, etc.)
8. CLNDs or SLs (before evaluation of the current melanoma) that may have altered the lymphatic drainage pattern from the primary cutaneous melanoma to a potential LN basin.
9. Organic brain syndrome or significant impairment of basal cognitive function or any psychiatric disorder that might preclude participation in the full protocol, or be exacerbated by therapy (e.g., severe depression).
10. Melanoma-related operative procedures not corresponding to criteria described in the protocol.
11. Primary or secondary immune deficiencies or known significant autoimmune disease.
12. History of organ transplantation.
13. Oral or parenteral immunosuppressive agents (not topical or inhaled steroids) at any time during study participation or within 6 months prior to enrollment.
14. Pregnant or lactating women.
15. Participation in concurrent therapy protocols of alternative local nodal basin therapies that might confound the analysis of this trial is not permitted. For example, radiation of a non-resected node basin is not acceptable because it might influence outgrowth of residual melanoma in that nodal basin. However, systemic adjuvant therapy or clinical trial adjuvant protocols after the finding of a positive node on LM/SL or delayed nodal recurrence in the ultrasound observation arm are both acceptable according to the standard of care at the multicenter site. Patients with positive sentinel nodes or thick primary melanomas who are considered by the multicenter site's investigator as high-risk may receive systemic adjuvant therapy according to the standard practice of that particular site.
16. SLND pathology shows, on microscopic examination, that melanoma extends through the lymph node capsule into the adjacent soft tissue.