Background In patients with non-ST elevation acute coronary syndrome (NST-ACS) that is treated invasively, glycoprotein (GP) IIb/IIIa inhibitors can be used either as upstream treatment in a coronary care unit or as downstream provisional treatment in selected patients who are undergoing percutaneous coronary intervention (PCI). The relative advantage of either strategy is unknown. The purpose of this study was to assess 30-day outcome of patients enrolled in a prospective NST-ACS registry and treated invasively with either of these two therapeutic strategies. Methods Patients treated invasively (coronary arteriography within 4 days of admission), in the prospective registry ROSAI-2, were divided into two groups according to the upstream use of GPIIb/IIIa inhibitors (n = 241), or not (n = 548). In the latter group, 76 (14%) patients received GPIIb/IIIa in association with a PCI procedure. Clinical and angiographic characteristics as well as in-hospital and 30-day outcome of these two groups of patients were compared. Results The two groups were similar with respect to age, sex, presence of hypertension, diabetes, number of PCI procedures. However, patients treated with upstream GPllb/llla blockers had more frequently ST-segment depression (P = 0.002), a high TIMI risk score (P = 0.01) and were more frequently admitted to centres with Cath Lab facilities (P = 0.001). At 30-day follow-up, the composite of death, acute myocardial infarction and stroke, as well as major bleeding, was not significantly different between the two groups, although it occurred more frequently in patients who received upstream GPIIb/IIIa blockers (9.5% versus 5.7% and 1.7% versus 0.2%, respectively). By multivariate analysis, diabetes [odds ratio (OR) = 2.22, 95% confidence interval (CI) = 1.2-4.09] and a diagnosis on admission of non-Q-wave myocardial infarction (OR = 2.0, 95% Cl = 1.10-3.6) were independently related to outcome. No additional risk or benefit was related to upstream GPIIb/IIIa inhibitor treatment (OR = 1.5, 95% Cl = 0.84-2.68). Conclusions Among invasively-treated patients with NST-ACS, upstream treatment with GPIIb/IIIa inhibitors was used in those with a higher clinical risk profile, whereas downstream treatment was reserved for a limited number of patients undergoing PCI. Thirty-day outcome was similar in the two groups, irrespective of the treatment strategy used.