In term infants sucrose given by mouth has been reported to reduce duration of crying after a heel prick. This study was designed primarily to investigate the effect of sucrose administered orally immediately before heel lancing on the nociceptive reaction in preterm infants as assessed by change in heart rate and duration of crying. A secondary objective was to document changes in cerebral blood volume during acute pain. We used a randomized, masked, placebo-controlled, crossover trial in a neonatal intermediate care unit in a level 3 perinatal center. The patients studied were 16 preterm infants; birth weight, 900–1900 g; gestational wk, 27–34; corrected postmenstrual age at time of investigation, 33–36 wk. Each infant was assessed twice receiving 2 mL of sucrose 50% or 2 mL of distilled water in random order immediately before heel lance. Heart rate, thoracic movements, and transcutaneous blood gases were monitored continuously. Crying during the procedure was documented by a video-camera. A change in cerebral blood volume was assessed by near-infrared spectroscopy. We found the heart rate increased by a mean of 35 beats/min (bpm) after sucrose and 51 bpm after placebo (median difference 16 bpm, interquartile range 1–30 bpm,p= 0.005). Infants cried 67% of time after sucrose and 88% after placebo (median difference 10%, interquartile range 3–33%,p= 0.002). Cerebral blood volume decreased in 5 of 14 infants after sucrose and in 6 of 14 infants after placebo (difference not significant). We concluded that sucrose administered orally before a heel lance reduces the pain reaction in preterm infants. Response of cerebral blood volume to pain does not seem to be altered by sucrose.