The present study focused on factors that predict students’ difficulties with process diagrams. 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 (i.e., 1- cohort mean exam score) of that particular task. 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. Interaction effects were found between the cognitive task demand and features of the student and the diagram. The final model explained 46 percent of the variance in exam scores.