Cutaneous melanoma is one of the leading causes of cancer-related death. Malignant transformation of epidermal melanocytes is a multifactorial process involving cell cycle and death control pathways. The purpose of this study was to analyze the immunohistochemical expression of cell-cycle-related and apoptosis-related proteins in cutaneous superficial spreading melanomas using the tissue microarray technique to further understand tumor development. A total of 20 samples of in-situ melanomas and 44 melanomas ≤1.0 mm were analyzed in conventional sections whereas 72 melanomas greater than 1.0 mm and 29 metastases were evaluated by tissue microarray. The sections were stained for the following proteins: p16INK4 (p16), cyclin D1, cyclin-dependent kinase 4 (Cdk4), retinoblastoma protein, tumor suppressor protein p53, and p21 cell cycle regulator (p21) using a streptavidine-biotin-peroxidase technique for immunohistochemistry. Thick melanomas (>1.0 mm) and metastases lost p16 expression in 100% of the cases and in-situ and thin melanomas (≤1.0 mm) had low rate of p16 expression (7.9%). When comparing thin versus thick melanomas, thin melanomas showed higher expression of cyclin D1 and cytoplasmatic Cdk4, and thick melanomas had increased expression of nuclear Cdk4, tumor suppressor protein p53, and p21. Primary tumors, when compared with metastases, had higher cytoplasmatic Cdk4 expression. None of the studied proteins influenced overall or disease-free survival. Our results suggest that loss of p16 expression was a constant feature in primary and metastatic melanomas. Cyclin D1 expression seems to be related to initial phases of melanoma development. An increase in p21 expression could represent a cell cycle control in proliferating cells with reduced p16 and/or increased nuclear Cdk4 expression.