Purpose. The purpose of this review was to assess effectiveness of nonsurgical treatment on irritable behavior of infants with gastroesophageal reflux disease. Design and Methods. A systematic literature review was conducted. Results. Research targeted treatment for irritability in infants with gastroesophageal reflux disease. All interventions including placebo were similar in reducing irritability. Which specific intervention is best for which infant is not yet known. Minor adverse effects that could increase discomfort in infants were found with pharmacologic treatments. Practice Implications. Knowledge of the effects of treatment on irritability and regurgitation can assist the nurse to work with other care providers in deciding how best to treat an individual infant.