L-cysteine is thought to be a conditionally essential (i.e., essential under certain conditions) amino acid for neonates. It is a precursor of glutathione, an antioxidant that may reduce oxidation injury. The addition of cysteine to parenteral nutrition (PN) allows for the reduction of the amount of methionine in PN, thereby limiting hepatotoxicity, and acidifies the solution, thereby increasing calcium and phosphate solubility, and potentially improving bone mineralization. To determine the effects of supplementing parenteral nutrition with cysteine, cystine or its precursor N-acetylcysteine on neonatal growth and short and long-term outcomes. The standard search method of the Cochrane Neonatal Review Group was used. MEDLINE (1966-December 2005), EMBASE (1974-December 2005), the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2006) and recent abstracts (until December 2005) from the Society for Pediatric Research/American Pediatric Society, Eastern Society for Pediatric Research, and Society for Parenteral and Enteral Nutrition were searched. All randomized (RCTs) and quasi-randomized trials that examined the effects of cysteine, cystine or N-acetylcysteine supplementation of neonatal PN were reviewed. Predetermined outcome variables included growth, nitrogen retention, mortality, morbidity secondary to oxidation injury, bone accretion, acidosis, liver disease, and cysteine levels. The standard methods of the Cochrane Collaboration and its Neonatal Review Group were used. Statistical analysis included relative risk, risk difference, and weighted mean difference (WMD). Six trials fulfilled entry criteria. The majority of patients in these trials were preterm. Five small trials evaluated short-term cysteine supplementation of cysteine-free PN. One large multicenter RCT evaluated short-term N-acetylcysteine supplementation of cysteine-containing PN in extremely low birth weight infants (< or = 1000 grams). Growth was not significantly affected by cysteine supplementation (evaluated in one quasi-randomized trial) or by N-acetylcysteine supplementation (evaluated in one RCT). Nitrogen retention was significantly increased by cysteine supplementation (studied in four trials) (WMD 31.8 mg/kg/day, 95% confidence interval +8.2, +55.4, n = 95, including 73 preterm infants). Plasma levels of cysteine were significantly increased by cysteine supplementation but not by N-acetylcysteine supplementation. N-acetylcysteine supplementation did not significantly affect the risks of death by 36 postmenstrual weeks, bronchopulmonary dysplasia (BPD), death or BPD, retinopathy of prematurity (ROP), severe ROP, necrotizing enterocolitis requiring surgery, periventricular leukomalacia, intraventricular hemorrhage (IVH), or severe IVH. No data were available on other outcomes. Available evidence from RCTs shows that routine short-term cysteine chloride supplementation of cysteine-free PN in preterm infants improves nitrogen balance.However, there is insufficient evidence to assess the risks of cysteine supplementation, especially regarding metabolic acidosis, which has been reported during the first two weeks of cysteine chloride administration. Available evidence from a large RCT trial does not support routine N-acetylcysteine supplementation of cysteine-containing PN in extremely low birth weight infants. A large RCT would be required to assess whether routine prolonged cysteine supplementation of cysteine-free PN affects growth and short and long-term neonatal outcomes in very low birth weight infants.