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Preterm infants (PI) requiring the neonatal intensive care unit are exposed to early repetitive pain/distress. Little is known about how pain relief strategies interact with infants’ clinical health status, such as severity of illness with pain responses. This study aimed to examine main and interactive effects of routine sucrose intervention and neonatal clinical risk (NCR) on biobehavioral pain reactivity-recovery in PI during painful blood collection procedures.Very low birth weight PI (<1500 g; n=104) were assigned to low and high clinical risk groups, according to the Clinical Risk Index for Babies. Sucrose group (n=52) received sucrose solution (25%; 0.5 mL/kg) 2 minutes before the procedures and control group received standard care. Biobehavioral pain reactivity-recovery was assessed according to the Neonatal Facial Coding System, sleep-wake state scale, crying time, and heart rate at 5 phases (baseline, antisepsis, puncture (P), recovery-dressing, and recovery-resting [R]). Repeated measure ANOVA with mixed-design was performed considering pain assessment phases, intervention group, and NCR.Independent of NCR, sucrose presented main effect in decreasing neonates’ facial activity pain responses and crying time, during P and R. Independent of NCR level or routine sucrose intervention, all neonates displayed activated state in P and decreased biobehavioral responses in R phase. Although no sucrose or NCR effects were observed on physiological reactivity, all neonates exhibited physiological recovery 10 minutes after P, reaching the same heart rate patterns as the baseline.Independent of NCR level, sucrose intervention for pain relief during acute painful procedures was effective to reduce pain intensity and increase biobehavioral regulation.