Purpose:To evaluate patient setup accuracy and quantify individual and cumulative positioning uncertainties associated with different hardware and software components of the stereotactic radiotherapy (SRS/SRT) with the frameless‐6D‐ExacTrac system.Methods:A statistical model was used to evaluate positioning uncertainties of the different components of SRS/SRT treatment with the BrainLAB 6D‐ExacTrac system using the positioning shifts of 35 patients having cranial lesions (49 total lesions treated in 1, 3, 5 fractions). All these patients were immobilized with rigid head‐and‐neck masks, simulated with BrainLAB‐localizer and planned with iPlan treatment planning system. Infrared imaging (IR) was used initially to setup patients. Then, stereoscopic x‐ray images (XC) were acquired and registered to corresponding digitally‐reconstructed‐radiographs using bony‐anatomy matching to calculate 6D‐translational and rotational shifts. When the shifts were within tolerance (0.7mm and 1°), treatment was initiated. Otherwise corrections were applied and additional x‐rays were acquired (XV) to verify that patient position was within tolerance.Results:The uncertainties from the mask, localizer, IR‐frame, x‐ray imaging, MV and kV isocentricity were quantified individually. Mask uncertainty (Translational: Lateral, Longitudinal, Vertical; Rotational: Pitch, Roll, Yaw) was the largest and varied with patients in the range (−1.05−1.50mm, −5.06–3.57mm, −5.51−3.49mm; −1.40−2.40°, −1.24−1.74°, and −2.43−1.90°) obtained from mean of XC shifts for each patient. Setup uncertainty in IR positioning (0.88,2.12,1.40mm, and 0.64,0.83,0.96°) was extracted from standard‐deviation of XC. Systematic uncertainties of the localizer (−0.03,−0.01,0.03mm, and −0.03,0.00,−0.01°) and frame (0.18,0.25,−1.27mm,−0.32,0.18, and 0.47°) were extracted from means of all XV setups and mean of all XC distributions, respectively. Uncertainties in isocentricity of the MV radiotherapy machine were (0.27,0.24,0.34mm) and kV‐imager (0.15,−0.4,0.21mm).Conclusion:A statistical model was developed to evaluate the individual and cumulative systematic and random uncertainties induced by the different hardware and software components of the 6D‐ExacTrac‐system. The immobilization mask was associated with the largest positioning uncertainty.