Objective: The differential diagnosis between retinal detachment and melanoma metastatic to the vitreous can be challenging, both clinically and cytologically. We demonstrate the diagnostic features and pitfalls of the cytological assessment. Study Design: A case of a metastatic melanoma to the vitreous is compared to a case of retinal detachment initially suspected as melanoma metastasis. Case 1 was a 54-year-old patient with a vague history of pigmented lesions 20 years previously and a current presentation of a visual defect. Case 2 was a 68-year-old patient with a history of melanoma and a presentation of floaters and flashing lights. Results: The vitreous fluid of case 1 contained atypical, pigment-laden cells positive for HMB-45 and assessed as melanoma. On enucleation, a melanoma metastatic to the vitreous was diagnosed. The vitreous fluid of case 2 revealed atypical cells containing pigment granules. The cells were negative for melanocytic markers, while the granules stained positive for melanin. Macrophage marker CD163 was positive in all cells. The interpretation was one of macrophages reactive to the retinal detachment. Conclusion: Melanin-laden macrophages can mimic melanoma cells. This needs to be considered in the differential diagnosis. Additional stains can help the distinction.