Using a non-invasive laser Doppler technique, we have previously shown that changes in SBF (in ml/100 gm) accurately reflect the experience of pain and discomfort in newborn infants (Early Human Development, 1995; 41:147, & Neurological Research, 1996; 18:440). In this study we tested whether pre-application of EMLA cream attenuates heelstick-induced pain as reflected in changes in SBF. After parental consent, infants were randomized either to a placebo (PL) cream group or to 5% EMLA group. The creams were dispensed in masked fashion. Approximately 2 gm cream was applied to heel with an occlusive dressing 60 min prior to a planned heelstick. Neither the nurse performing the heelstick nor the investigator measuring the blood flow knew the group assignment. Changes in SBF, heart rate (HR bpm), respiration rate (RR) and oxygen saturation (SO2) were recorded continuously. Results: Twenty-seven infants were randomized into the PL group and 30 into EMLA group. The distribution of gender, race, the median values for birth weight (1.28 kg), gestational age (29 & 29.5 wks), postnatal age (4 days), and mean (± SD) baseline SBF (18.4 ± 8.5 & 23± 14) were similar between groups. Application of either of the creams by itself prior to the heelstick procedure did not affect the SBF. Although its magnitude varied, heelstick procedures, which lasted 3.4 ± 1.9 min in PL, and 4.7 ± 2.2 min in EMLA group, caused a significant increase in SBF in both groups: 28.5 ± 54% in PL and 29.8 ± 40% in the EMLA group (P<0.001 compared to respective baselines, paired t test; but not significant between groups). Even after controlling for baseline differences EMLA use did not affect SBF (ANCOVA). By 15 min after heelstick, SBF was similar to baseline in both the groups. Changes in HR, RR, and SO2 were variable, but not statistically significant compared to respective baselines during heelstick. We conclude: 1) Heelstick procedures cause SBF increase in high risk infants, perhaps from pain and discomfort; 2) these changes are transient; 3) EMLA does not affect heelstick-induced changes in SBF, and hence, may be an ineffective analgesic for this purpose; and 4) SBF is a valuable research tool in assessing pain and discomfort in newborn infants.