Nitric oxide (NO) is reported to antagonize endotheline resulting in protection from ischemia-reperfusion injury. Additionally NO seems to play an important role in the phenomenon of ischemic preconditioning (IP). Previous studies regarding the role of NO in flap ischemia focus on late IP using sodium nitroprusside, or the role of L-arginine as a precursor of NO, and a substrate of the endothelial NO synthase. The purpose of this study is to determine whether flap survival can be improved by pre- or post-ischemic intravenous application of the new NO donor Spermine / Nitric Oxide Complex (Sper/NO) with a long half life (39 min in 37°C phosphate buffer pH 7.4), and a controlled biological release of NO in vivo. Thirty-seven male Wistar rats were divided into four experimental groups. An extended epigastric adipo-cutaneous flap (6x10cm) was raised in each animal. In one of the control groups (C, n=10), a three hour flap ischemia was induced by clamping the pedicle. Another group served as a non-ischemic control (CO, n=8). The animals of group S1 (n=10) received 500 nmol/kg Sper/NO intravenously 30 min prior to ischemia. In group S2 (n=9) an equivalent dose of Sper/NO was administered 5 min prior to reperfusion. Flap ischemia was induced in group S1, and S2 as in control group C. The mean flap necrosis area was assessed for all groups on the fifth postoperative day using planimetry software. Average flap necrosis area was 68.2% (±18.1%) in the control group C, and 29.7% (±13,3%) in the non-ischemic controls (CO). The group with pre-ischemic application of Sper/NO (S1) demonstrated with an average flap necrosis of 11.2% (±5.9%), whereas it was 59.2% (±14.4%) in group S2. Group S1 showed a significantly lower flap necrosis area than the groups C, CO, and S2 (p<0.05). Group S2 demonstrated a significantly higher mean flap necrosis area than the non-ischemic controls (p<0.05). However, no significant difference could be shown between the groups S2 and C. Our data show, that pharmacological ischemic preconditioning, and enhancement of flap survival can be achieved by intravenous administration of Sper/NO. The application of Sper/NO at the end of the ischemic period does not provide protection from ischemia. Our data suggest, that acute pharmacological ischemic preconditioning for improved flap survival could be performed simultaneously with or even prior to flap harvest in the clinical setting.