Ocular melanoma is the second most common melanoma type after the cutaneous variety and represents about 3.7% of all melanomas. Of these, 82.5% are uveal, 6.6% are conjunctival and 10.9% occur at other sites. It is a potentially lethal disease, especially when it results in metastatic spread. Conventional treatments include radiation (brachytherapy, teletherapy), transpupillary thermotherapy, surgical resection (partial or full), enucleation, chemotherapy, and immunotherapy, but recurrences are frequent, with high morbidity depending on the initial tumor size. Two-photon photodynamic therapy (2-PE PDT) involves the use of ultrashort (fs) long-wavelength (near-infrared, NIR) laser pulses to excite the photosensitizer rather than low-intensity continuous light. The advantage is that melanin has a low NIR absorption, improving the light penetration into the tumor. Our in vitro studies show that 2-PE PDT is more efficient in melanotic than in amelanotic melanoma cells, while the control 1-PE PDT gives similar responses in both cell lines. In vivo, using conjunctival melanomas grown in 10 mice, histology shows apoptosis only at the treatment site, with no damage to the surrounding normal tissue. Also, in a single session, the technique could eliminate the entire tumor mass. These initial results suggest that 2-PE PDT has a high potential for the treatment of pigmented ocular melanomas and may represent a new alternative to conventional therapies.