Objectives: To demonstrate how human-machine intelligence can be integrated for efficient image analysis of drusen in age-related macular degeneration and to validate the method in 2 large, independently graded, population- based data sets. Methods: We studied 358 manually graded color slides from the Netherlands Genetic Isolate Study. All slides were digitized and analyzed with a user-interactive drusen detection algorithm for the presence and quantity of small, intermediate, and large drusen. A graphic user interface was used to preprocess the images, choose a region of interest, select appropriate corrective filters for images with photographic artifacts or prominent choroidal pattern, and perform drusen segmentation. Weighted kappa statistics were used to analyze the initial concordance between human graders and the drusen detection algorithm; discordant grades from 177 left-eye slides were subjected to exhaustive analysis of causes of disagreement and adjudication. To validate our method further, we analyzed a second data set from our Columbia Macular Genetics Study. Results: The graphical user interface decreased the time required to process images in commercial software by 60.0%. After eliminating borderline size disagreements and applying corrective filters for photographic artifacts and choroidal pattern, the weighted kappa values were 0.61, 0.62, and 0.76 for small, intermediate, and large drusen, respectively. Our second data set demonstrated a similarly high concordance. Conclusions: Drusen identification performed by our user-interactive method presented fair to good agreement with human graders after filters for common sources of error were applied. This approach exploits a synergistic relationship between the intelligent user and machine computational power, enabling fast and accurate quantitative retinal image analysis.