We report our experience of percutaneous coronary intervention (PCI) with 5 French (Fr) guiding catheters in a retrospective analysis of consecutive cases undergoing ad hoc PCI. Results were compared with a cohort of 6 Fr PCI cases matched for age, sex and operator over the same study period. A total of 210 patients (311 lesions) underwent PCI using 5 Fr guiding catheters and 174 matched patients (300 lesions) underwent PCI with 6 Fr guiding catheters. Multivessel PCI was performed in 18% of patients in the 5 Fr group and in 26% of the 6 Fr group (p = 0.046). There was no difference in clinical, angiographic or procedural characteristics between groups. Technical success rate was superior in the 5 Fr group compared with the 6 Fr (99% versus 95%; p = 0.03). The rate of stent implantation did not differ and the 5 Fr guiding catheter did not prohibit the use of large or long stents/balloons. Failure of 5 Fr PCI in 3 cases was not due to inadequate guiding catheter support. In-hospital major adverse cardiac events (MACE) and serious femoral complications were rare and at 6-month follow-up did not differ between groups. However, compared with 6 Fr PCI, procedure time and contrast medium usage was significantly less in the 5 Fr group (contrast: 274 +/- 101 ml versus 313 +/- 124 ml; p = 0.0008; fluoroscopy time: 16 +/- 9 minutes versus 19 +/- 12 minutes; p = 0.006). We conclude that the use of 5 Fr guiding catheters is effective and safe in unselected patients undergoing PCI and may even confer certain advantages. The 5 Fr approach can be recommended for routine interventional practice.