Students in secondary science education seem to have difficulties with understanding diagrams. The present study focused on explanatory factors that predict students' difficulties with process diagrams, i.e., diagrams that describe a process consisting of components that are related by arrows. From 18 compulsory national Biology exams of secondary school pre-university students, all process diagram tasks (n = 64) were included in corpus. Features of the task, student, and diagram were related to the difficulty of that particular task, indicated by the cohort mean exam score. A hierarchical regression analysis showed main effects for (1) the cognitive task demand, (2) the familiarity of the components, and (3) the number of components in a diagram. All these main effects were in the expected direction. We also observed interactions. Within the category of tasks with a high cognitive demand, tasks about a diagram of which students have low prior content knowledge were more difficult than tasks about a diagram of which students have high prior content knowledge. Tasks with a high cognitive demand about a diagram with familiar arrows were, surprisingly, more difficult than tasks with a high cognitive demand about a diagram with unfamiliar arrows. This latter finding might be attributed to compensation for task difficulty by the large number of components in the diagrams involved. The final model explained 46 % of the variance in exam scores. These results suggest that students have difficulties (1) with tasks that require a deeper understanding when the content is new, (2) with diagrams that use unfamiliar component conventions, and (3) with diagrams that have a small number of components and are therefore probably more abstract.