Accurate quantification of retinal structures in 3-D optical coherence tomography data of eyes with pathologies provides clinically relevant information. We present an approach to jointly segment retinal layers and lesions in eyes with topology-disrupting retinal diseases by a loosely coupled level set framework. In the new approach, lesions are modeled as an additional space-variant layer delineated by auxiliary interfaces. Furthermore, the segmentation of interfaces is steered by local differences in the signal between adjacent retinal layers, thereby allowing the approach to handle local intensity variations. The accuracy of the proposed method of both layer and lesion segmentation has been evaluated on eyes affected by central serous retinopathy and age-related macular degeneration. In addition, layer segmentation of the proposed approach was evaluated on eyes without topology-disrupting retinal diseases. Good agreement between the segmentation performed manually by a medical doctor and results obtained from the automatic segmentation was found for all data types. The mean unsigned error for all interfaces varied between 2.3 and 11.9 μm (0.6-3.1 pixels). Furthermore, lesion segmentation showed a Dice coefficient of 0.68 for drusen and 0.89 for fluid pockets. Overall, the method provides a flexible and accurate solution to jointly segment lesions and retinal layers.