In the past decade, our knowledge of pain in newborn infants has advanced considerably. However, infants at significant risk for neurologic impairment (NI) have been systematically excluded from almost all research on pain in neonates. The objectives of this study were to compare: (a). the nature, frequency and prevalence of painful procedures, (b). analgesics and sedatives administered, and (c). the relationship between painful procedures and analgesia for neonates at risk for NI. One hundred and ninety-four infants at high (cohort A, n=67), moderate (cohort B, n=59) and low (cohort C, n=68) risk for NI from two tertiary level Neonatal Intensive Care Unit's in Canada were included in a retrospective cohort study on the first 7 days of life. Data were collected from medical records and analyzed using chi-square, ANOVA and regression approaches. All cohorts had a mean of >10 painful procedures per day during the first 2 days of life. There was an interaction effect between cohort group and day of life (F(5,188)=2.13, P<0.06) with cohort A having significantly more painful procedures on day 1 (F(2,191)=4.79, P<0.009). There was no statistical difference in the number of infants who received continuous infusion (F(2,20)=1.9, P=0.13) or bolus (F(2,20)=1.3, P=0.25) opioids or sedatives (F(2,20)=0.45, P=0.84) by cohort over the 7 day period. There was a statistical difference in bolus opioid administration for days 1 (P<0.05) and 2 (P<0.001) with less than 10% of infants in cohort A receiving bolus opioids compared with approximately 22-33% of infants in cohorts B and C. There was a statistically significant correlation between painful procedures and analgesic use (r=0.29, P<0.001), although significant associations existed for cohorts B and C only. The number of painful procedures and study site primarily accounted for the variance (61% in cohort B and 35% in cohort C) in analgesic use, while in cohort A, only study site contributed to the variance (16%). Neonates at the highest risk for NI had the greatest number of painful procedures and the least amount of opioids administered during the first day of life. There was no relationship between painful procedures and analgesic use in this group. As these infants are vulnerable to pain and its consequences, the rational underlying health professional strategies regarding painful procedures and analgesic use for procedural pain in this population urgently awaits exploration.