Measurement of fractional flow reserve (FFR) with a pressure wire is used to discriminate between patients with and without functionally significant lesions. FFR can be assessed through a conventional 4Fr diagnostic catheter, which is a more convenient method of assessment. The aim of this study was to assess the feasibility, safety, repeatability, and reliability of routine FFR measurements through 4Fr diagnostic catheters. From a single-center prospective registry, results of FFR assessment through a 4Fr catheter were used to determine: (1) feasibility and safety, by the procedural success rate and immediate and 30-day clinical outcome; (2) repeatability, by the intraclass correlation coefficient and comparison of the difference (means ± 2 SDs); and (3) reliability, by comparison of results obtained using 4Fr versus 7Fr guiding catheters. During the study period, FFR was measured in 190 patients, in 122 using a diagnostic 4Fr catheter (study population) and in 68 using a 7Fr guiding catheter. Measurement of FFR wa successful in 115 of 122 patients (94%). No complications related to the use of the 4Fr catheter occurred. Repeatability was determined from 108 repeated measurements: the intraclass correlation coefficient was 0.942 and the mean difference between repeated FFR measurements was −0.001 ± 0.038. Reliability was determined from 15 unselected patients; there was no systematic error and only 1 value was out of the range of 2 SDs of the mean difference. Using a threshold value of 0.75, the Kappa coefficient for the qualitative agreement was 0.84. Thus, pressure-derived FFR assessment can safely be performed through 4Fr diagnostic catheters, with similar repeatability and reliability as 7Fr guiding catheters, resulting in a simplification of the measurement procedure.