BACKGROUND: Fractional flow reserve (FFR) may yield false-negative results in up to 12% of lesions tested, and there is a zone of uncertainty at borderline values. METHODS: Forty-eight patients were investigated by means of dobutamine stress echocardiography (DSE), coronary angiography, and FFR assessment of 48 coronary lesions before, during, and immediately after handgrip exercise. RESULTS: Mean FFR values were lower during and immediately after handgrip exercise as compared with baseline (0.86 +/- 0.09 vs 0.87 +/- 0.08 vs 0.88 +/- 0.08, P < .05, respectively). The sensitivity of FFR < or = 0.75 for predicting myocardial ischemia on DSE was 17.6% before handgrip exercise, 52.9% during, and 35.5% immediately after exercise. The specificity of FFR < or = 0.75 before, during, and immediate after exercise was 100%, 93.5%, and 96.8%, respectively. In 10 patients, FFR values > 0.75 before handgrip became < or = 0.75 during or immediately after handgrip exercise (P = .01). All these patients had angina and/or DSE indicating ischemia in the territory of the vessel studied, and underwent coronary intervention. At 6 months follow-up, all patients were asymptomatic with negative DSE tests. CONCLUSIONS: The addition of handgrip exercise can significantly lower the FFR and potentially improve its ability to detect physiologically significant stenoses.