Abstract: Objective: To evaluate the effect of different focal spot sizes on image quality in 64-row MDCT brain imaging. Method: Plain cranial axial CT scans were performed on twenty healthy volunteers with GE LightSpeed VCT (64×0.625 mm detectors, small focal spot size 0.6 mm×0.7 mm, large focal spot size 0.9 mm×0.9 mm). Informed consents were obtained in all volunteers. Axial scans across the posterior cranial fossa were performed with different focal spots on all subjects, with the other parameters not changed. The images were printed at the same window setting with Kodak Dryview 8700 laser imager and reviewed by two radiologists to rate the artifacts of bony structures at posterior cranial fossa. The results were analyzed with SPSS 11.5 for Kappa test and intragroup Chi-square test. Results: The two radiologists were in accordance with the rating of the artifacts at posterior cranial fossa (Kappa = 0.57). Less artifacts were observed at posterior cranial fossa with small focal spots than with large focal spots (P<0.05). Conclusion: Artifacts of cranial base can be reduced by using small focal spots on 64-row MDCT brain scan. Using small focal spot in clinical examination, better image quality can be achieved in brain CT scan.