This chapter provides an example of how uncertainty about the origin of a neonatal disorder, retinopathy of prematurity (ROP), can be reduced. Retinopathy of prematurity is a complex neonatal disorder with multiple contributing factors. In this chapter I use the model of etiological explanation and combined contribution to mount the evidence in support of the proposal that neonatal sepsis meets all requirements for being a cause of ROP (not a condition, mechanism, or even innocent bystander) by means of initiating the early stages of the patho-mechanism of ROP occurrence, systemic inflammation. It can be shown that sepsis can initiate the early stages of the patho-mechanism via systemic inflammation (causation process) and that systemic inflammation can contribute to growth factor aberrations and the retinal characteristics of ROP (disease process). The combined combination of these factors with immaturity at birth (as intrinsic risk modifier) and prenatal inflammation (as extrinsic modifier) seems to provide a cogent functional framework of ROP occurrence. Finally, I apply the Bradford Hill’s heuristics to the available evidence as a quasi-causometer. Taken together, the evidence suggests that neonatal sepsis is a causal initiator of ROP.