This optimization treats 2D and 3D single‐slab Time‐Of‐Flight (TOF) as opposite limiting cases of MOTSA. It was approached from a general theoretical analysis through imaging parameters such as flow velocity, T1 of blood and surrounding tissue, and size of the region of interest. The potential CNR improvement from using magnetization transfer contrast (MTC) in conjunction with the MOTSA sequence was also examined. A mathematical model was built and tested to describe evolution of hydrogen magnetization under radio frequency pulses, and the computer simulations in turn were used to determine an optimized combination of flip angle, repetition time (TR) and slab thickness. A flat slab‐selection profile was used, under the constraints of fixed anatomical coverage, total acquisition time and resolution. Results of phantom and volunteer studies agree with the computer simulation. Conclusions of this study are (1) the flow model used is adequate for imaging the human anterior cerebral arteries, a representative of intracranial arteries; (2) combination of MTC (using a binomial pulse) with MOTSA does not improve CNR; (3) the optimum MOTSA technique has the shortest TR possible, a slab thickness in which flowing blood receives approximately two flips, and a flip angle chosen to yield the maximum vessel‐to‐background CNR for that particular TR and slab thickness.