Cyclin F is a non-canonical cyclin which is a part of the SKP1-CUL1-F-box protein (SCF) E3 ubiquitin-protein ligase complex. Cyclin F is responsible for target recognition, ubiquitination, and degradation of various molecular targets. This protein also controls genome stability through the degradation of ribonucleotide reductase subunit M2 (RRM2). In the present study, the difference between cyclin F expression in cell lines derived from primary and metastatic melanoma, A375 and RPMI-7951, respectively, were investigated using a western blot analysis and flow cytometry assays. A decrease in cyclin F expression in the A375 cells and an increase in RPMI-7951 cells after cisplatin treatment were observed. These changes may be related to a mutation in p53 in the RPMI-7951 cell line. Flow cytometry was conducted to observe that the RPMI-7951 cell line exhibited greater susceptibility to cisplatin, associated with lack of proper cell cycle control. Therefore, it is possible that cyclin F may modulate drug response in melanoma. The presented data describe cyclin F as a new potential factor that contributes to drug resistance in melanoma patients.