Background: S-phase kinase associated protein- 2 (Skp2) ubiquitin ligase p 45SKP2 is important in the degradation of p27kip1 (a cyclin dependent kinase inh ibitor) and progression through the G1- S cell-cycle checkpoint. Low levels o f p27 and high levels of Skp2 are related to poor prognosis in some cancers. Met hods: Clinicopathologic features and immunohistochemical expression of Skp2 and p27kip1 were investigated in 198 melanocytic proliferations: 21 melanocytic nevi , 23 melanoma in situ, 119 primary melanoma, and 35 metastatic melanoma samples. Comparative and survival analyses were performed. Results: Progressive and sign ificant increases and decreases in the nuclear expression of Skp2 and p27kip1, r espectively, was identified moving from melanocytic nevi (0.05 ± 0.2/85 ± 15 ) to melanoma in situ (3 ± 2/45 ± 20) to primary cutaneous melanoma (12 ± 9/30 ± 25) to metastatic melanoma (25 ± 15/15 ± 20) (P ≤ 0.006). Express ion of these proteins also significantly correlated with increasing American Joi nt Committee on Cancer (AJCC) T (tumor) classification and AJCC stage (P ≤ 0.0 1). Moreover, the level of these two proteins exhibited a significant inverse re lationship (r =- 0.4, P=0.0001). Skp2 cytoplasmic labeling index of > 20% pre dicted worse 10- year overall survival (38% vs. 86% , P=0.04) in primary mel anoma. Neither p27 nor Skp2 nuclear expression impacted significantly on prognos is. Conclusions: Gain of Skp2 and loss of p27kip1 protein expression are implica ted in melanoma progression where the level of p27kip1 may be regulated by targe ted proteolysis via Skp2. Cytoplasmic expression of Skp2 defines a subset of agg ressive melanomas and could represent another pathway of deregulation of the cel l cycle. Background: S-phase kinase associated protein-2 (Skp2) ubiquitin ligase p 45SKP2 is important in the degradation of p27kip1 (a cyclin dependent kinase inhbitor) and progression through the G1-S cell-cycle checkpoint. Low levels of p27 and high Levels of Skp2 are related to poor prognosis in some cancers. Met hods: Clinicopathologic features and immunohistochemical expression of Skp2 and p27kip1 were investigated in 198 melanocytic proliferations: 21 melanocytic nevi, 23 melanoma in situ, 119 primary melanoma, and 35 metastatic melanoma samples. Comparative and survival analyzes were performed. Results: Progressive and significant increases and decreases in the nuclear expression of Skp2 and p27kip1, espectively, was identified moving from melanocytic nevi (0.05 ± 0.2 / 85 ± 15) to melanoma in situ (3 ± 2 of 45 ± 20) to primary cutaneous melanoma (12 ± 9/30 ± 25) to metastatic melanoma (25 ± 15/15 ± 20) (P ≦ 0.006). Express ion of these proteins also significantly correlala ted with increasing American Joining Committee on Cancer (AJCC) T (tumor) classification and AJCC stage (P ≤ 0.0 1). Moreover, the level of these two proteins shows a significant inverse re lationship (r = -0.4, ). Neither p27 nor Skp2 nuclear expression impacted significantly on prognos is. Conclusions: Gains of> 20% pre dicted worse for 10-year overall survival (38% vs. 86%, P = 0.04) of Skp2 and loss of p27kip1 protein expression are implica ted in melanoma progression where the level of p27kip1 may be regulated by targe ted proteolysis via Skp2. Cytoplasmic expression of Skp2 defines a subset of agg ressive melanomas and could represent another pathway of deregulation of the cel l cycle.