To understand how the ‘caregiving context’ could affect responses to procedural pain, the authors sought to determine whether (1) the combined effects of sweet taste and holding (caregiving contact) were greater than the effects of either alone, (2) any combined effects were additive or interactive, and (3) the interventions had similar effects on behavioral (crying and facial activity) and physiological (heart rate, vagal tone) responses to the heel-stick procedure in newborn infants in a randomized two-factorial intervention trial. Eighty-five normally developing newborn infants were studied with a mean gestational age of 39.4 weeks on the 2nd or 3rd day of life. Infants were randomized in blocks of eight to receive (1) no holding and water taste (control participants), (2) no holding and sucrose taste (sucrose group), (3) holding and water taste (holding group), or (4) holding and sucrose taste (holding and sucrose group). Crying was reduced significantly by taste and holding, and the interventions combined additively. Facial activity was only significantly reduced by holding. For physiological measures, the interventions interacted with each other and preintervention levels to reduce heart rate and lower vagal tone more during the procedure in infants in whom heart rate and vagal tone were higher before intervention. Consequently, sweet taste and holding interventions combined in complex ways when acting on different behavioral and physiological response systems to modify stressful pain experiences. The results suggest that providing a caregiving context when painful procedures are performed may be a simple and practical method of reducing pain experience in infants, and that no one measure captures these effects.