Thrombocytopenia, both at baseline and acquired throughout admission is associated with poor clinical outcomes in patients with coronary artery disease. It is not known whether severe thrombocytopenia in patients receiving glycoprotein IIb/IIIa inhibitors (GPI) carries the same risk as thrombocytopenia from other aetiologies. We identified 50 consecutive patients referred for percutaneous coronary intervention (PCI) who developed severe thrombocytopenia (<50 × 10(9) cells/l) and followed their clinical course to 30 days. Two groups were compared: (1) severe thrombocytopenia following GPI usage and (2) severe thrombocytopenia without exposure to GPI. Baseline platelet counts were higher in GPI group (201 ± 62 vs. 112 ± 83 × 10(9) cells/l, p < 0.05). Patients in GPI group had more profound thrombocytopenia yet quicker recovery of platelet counts. The GPI group received fewer blood product transfusions (red cells: 0.1 ± 0.4 vs. 1.3 ± 2.0, p < 0.05, platelets: 0.22 ± 0.6 vs. 1.1 ± 1.7, p < 0.05) and had lower event rates for the primary end point of 30-day mortality (3.7% vs. 42.1%, p < 0.05), and for major bleeding (0% vs. 15.8%, p < 0.05). In conclusion, GPI associated severe thrombocytopenia follows a distinct clinical course when compared to severe thrombocytopenia due to other aetiologies. Our results suggest that patients who develop severe thrombocytopenia following GPI therapy may be managed conservatively with careful monitoring.