Purpose To investigate the cone photoreceptor mosaic in eyes with pseudodrusen as evidenced by the presence of subretinal drusenoid deposits (SDD) and conventional drusen using adaptive optics (AO) imaging integrated into a multimodal imaging approach. Design Observational case series. Participants Eleven patients (11 eyes) with pseudodrusen and 6 patients (11 eyes) with conventional drusen. Methods Consecutive patients were examined using near-infrared reflectance (IR) confocal scanning laser ophthalmoscopy (SLO) and eye-tracked spectral-domain optical coherence tomography (SD-OCT) and flood-illuminated retinal AO camera of nonconfluent pseudodrusen or conventional drusen. Correlations were made between the IR-SLO, SD-OCT, and AO images. Cone density analysis was performed on AO images within 50 × 50-μm windows in 5 regions of interest overlying and in 5 located between SDD or conventional drusen with the same retinal eccentricity. Main Outcome Measures Cone densities in the regions of interest. Results The pseudodrusen correlated with subretinal accumulations of material in SD-OCT imaging and this was confirmed in the AO images. Defects in the overlying ellipsoid zone band as seen by SD-OCT were associated with SDD but not conventional drusen. The mean ± standard deviation cone density was 8964±2793 cones/mm2 between the SDD and 863±388 cones/mmÂ over the SDD, a 90.4% numerical reduction. By comparison the mean cone packing density was 9838±3723 cones/mmÂ on conventional drusen and 12 595±3323) cones/mmÂ between them, a 21.9% numerical reduction. The difference in cone density reduction between the two lesion types was highly significant (P < 0.001). Conclusions The pseudodrusen in these eyes correlated with subretinal deposition of material in multiple imaging modalities. Reduced visibility of cones overlying SDD in the AO images can be because of several possible causes, including a change in their orientation, an alteration of their cellular architecture, or absence of the cones themselves. All of these explanations imply that decreased cone photoreceptor function is possible, suggesting that eyes with pseudodrusen appearance may experience decreased retinal function in age-related macular degeneration independent of choroidal neovascularization or retinal pigment epithelial atrophy. © 2014 by the American Academy of Ophthalmology Published by Elsevier Inc.