Objectives <p>To evaluate the efficacy of oral <i>Lactobacillus rhamnosus</i> GG (LGG) in reducing neonatal enterocolitis (NEC), sepsis and mortality in very low birth weight (VLBW) infants.</p> Methods <p>This open-label randomized controlled trial included enterally-fed VLBW infants with gestational age ≤ 32&#xa0;weeks; those with gastrointestinal anomalies, severe birth asphyxia (APGAR score &lt; 3 at 5&#xa0;min), cyanotic congenital heart disease, and those not started on feeds by 14&#xa0;days of life were excluded. Participants were randomized to receive either no probiotic (control) group, or probiotic (LGG; intervention) group. The intervention group received the first dose of LGG (probiotic) at feed initiation and was continued till 35&#xa0;weeks of corrected gestational age. The control group received only breast milk. Clinical outcomes (mortality, NEC, sepsis) were compared in both groups during hospital stay.</p> Results <p>A total of 236 infants were enrolled. The primary composite outcome of sepsis, NEC or mortality was seen in 35 (30.4%) and 33 (27.2%) infants, respectively in the LGG and control groups (RR 0.85; 95%CI 0.48–1.50, <i>P</i> = 0.592). The mean (SD) time to reach full feeds was 11.9 (4.2) and 12.0 (5.5) days in the LGG and control groups, respectively; <i>P</i> = 0.561. The mean (SD) time to regain birth weight was 13.5 (3.9) and 13.6 (3.9) days in the LGG and control groups, respectively (<i>P</i> = 0.982). There was no significant difference in duration of hospital stay, duration of mechanical ventilation, or duration of antimicrobial therapy between the two groups (<i>P</i> &gt; 0.05).</p> Conclusions <p>Use of LGG as single component probiotic in VLBW infants did not confer any significant benefit on the composite outcome of mortality, sepsis or NEC.</p> Trial Registry <p>Clinical Trial Registry of India; Ref. No. CTRI/2021/03/031724 dated Mar 03, 2021.</p>