Neonatal hyperbilirubinemia is a common phenomenon during the first days after birth. However, severe hyperbilirubinemia may cause brain damage when not timely recognized and treated. Visual inspection, the traditional first-line approach to identifying hyperbilirubinemia, is unreliable. The STARSHIP trial was designed to assess the effectiveness of (a) daily screening for neonatal hyperbilirubinemia using transcutaneous bilirubin measurement in reducing severe hyperbilirubinemia, and (b) application of phototherapy in primary care in reducing hospital admissions. A factorial stepped-wedge cluster randomized controlled trial is conducted in primary care birth centers in the Netherlands. Each cluster starts with a control phase of “usual” care, followed by a phase in which one of the two interventions (i.e., daily transcutaneous bilirubin quantification or phototherapy in primary care) is applied. In the last phase, both interventions will be applied. The factorial design allows us to assess the effectiveness of two interventions in the same trial and is therefore time-efficient and cost-efficient. Both interventions will be implemented stepwise during the study. Toward the end of the trial, all clusters will have implemented both interventions. This offers the opportunity to learn from the implementation of the interventions during the study. Our initial experiences are that perinatal health care providers in the primary care setting are unfamiliar with conducting research, and extensive support is needed to assist them in their tasks. In this case study, these and other pros and cons of a factorial stepped-wedge cluster randomized controlled trial in primary care are outlined.