We aimed to evaluate the differences between exercise testing (ET), myocardial perfusion SPECT (MPS) and a combination of ET and MPS based risk assessment as outlined by the guidelines with respect to their "gate-keeper" role to coronary angiography (cath) and the associated diagnostic procedural costs if prognostic considerations, as those proposed by the current guidelines and the recent literature, were taken into account. The Duke-score and the summed difference score (SDS; extent of ischemia) were assessed in 955 consecutive patients referred for MPS combined with ET. According to the guidelines and the available literature, three different algorithms for risk stratification were retrospectively applied: (1) ET based risk stratification and cath if intermediate or high risk Duke-score; (2) MPS based risk stratification and cath if SDS ≥ 8; (3) combined approach with ET as first step and MPS in case of intermediate risk Duke-score. A cath would have been suggested in every patient with either high risk Duke-score or SDS ≥ 8 in patients with intermediate risk Duke-score. The referral rate to cath was 27% according to the ET alone, 13% using MPS, and finally 12% applying the combined risk stratification. The cost of the diagnostic work-up including cath were: 615€, 1,299€, and 598€ per patient, respectively. The coronary angiography referral rate widely depends on the diagnostic modality used for risk stratification and according to the referral criteria provided by the guidelines. In the present study, the use of a stress imaging modality (MPS) and published prognostic data was associated with a lower referral rate to cath as compared to exercise testing alone and thus underlines the advantage of a risk based approach applying stress imaging in patients with intermediate risk Duke-score.