The present study describes a case of a 9-year-old girl diagnosed on the autism spectrum who averaged nearly 1200 hand-to-head self-injuries (+attempts) per school day. Given the resources of the school and the significance of the self-injurious behavior (SIB), analog functional analysis is not possible. Moreover, functional assessment results were inconclusive. Subsequent analyses suggested a relationship between SIB and instructional conditions, which we evaluated in an alternating treatments design that manipulated task difficulty, rate, interspersal, novelty, and order of presentation. This sequential modification of instructional components ultimately produced a methodology that is associated with an approximately 90% reduction in SIB. The study illustrates a strategy for treatment decision making in cases of serious problem behavior and when traditional functional behavioral assessment and functional analysis are inconclusive.