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Purpose To compare vitreoretinal pathology imaged with portable handheld spectral domain optical coherence tomography (SDOCT) to conventional indirect ophthalmoscopic (IO) examination in neonates undergoing screening for retinopathy of prematurity (ROP). Methods SDOCT images were collected from 76 eyes of 38 neonates during 118 routine ROP examinations. Imaging sessions in the neonatal intensive care unit were performed immediately after the subjects underwent a standard ophthalmic examination with IO by a pediatric ophthalmologist. Masked certified SDOCT graders evaluated scans for preretinal and retinal findings including material in the vitreous, epiretinal membrane, intraretinal cystoid structures and deposits, optic nerve and vascular features, as well as severity and location of ROP. The frequency of detection of these features by clinical examination and evaluation of SDOCT images was compared to determine potential clinical advantages for each modality. Results Portable SDOCT imaging characterized macular features of retinal cystoid structures in 39% of exams and epiretinal membrane in 32% of exams. Neither feature was visualized by indirect ophthalmoscopy in any cases. The clinician using indirect ophthalmoscopy detected stage of ROP and the presence or absence of plus or pre-plus disease. These were not visualized with SDOCT. Conclusions SDOCT provides new information about the premature infant retina that is of unknown importance relative to visual development and acuity. As used in this study, SDOCT does not replace indirect ophthalmoscopy for evaluation of ROP.