PURPOSE: To demonstrate how current theories regarding ultrashort laser pulse effects may apply to ocular tissue, a prospective clinicopathologic study of macular lesions from ultrashort laser pulses compared the pathologic effects with the clinical and fluorescein angiographic appearance of the laser lesions. METHODS: Ninety-femtosecond, 3-picosecond, and 60-picosecond laser pulses, throughout a range of energies, were delivered to the retina of Macaca mulatta. Clinical examination and fluorescein angiography were performed at 1 hour in all eyes and 24 hours after exposure in selected eyes. Eyes were enucleated at 1 or 24 hours after lesion placement. The structure and extent of retinal lesions were scored for comparison with the clinical findings. RESULTS: Focal retinal pathologic appearance correlated well with a clinically visible lesion observed 24 hours after laser delivery. Retinal lesions were small foci of retinal pigment epithelium (RPE) and retinal disruption, without choriocapillaris involvement. Lesions that contained focal RPE vacuoles or lifting of the RPE also demonstrated leakage, in fluorescein angiographic studies. Suprathreshold laser delivery frequently caused focal columns of retinal injury and intraretinal hemorrhages from retinal vessel bleeding, with no rupture of choroidal blood vessels. CONCLUSIONS: The retinal response to ultrashort laser pulses at moderate energy followed a pattern of focal damage from laser-induced breakdown without significant thermal spread.