In magnetic resonance (MR)-targeted, 3-D transrectal ultrasound (TRUS)-guided biopsy, prostate motion during the procedure increases the needle targeting error and limits the ability to accurately sample MR-suspicious tumor volumes. The robustness of the 2-D-3-D registration methods for prostate motion compensation is impacted by local optima in the search space. In this paper, we analyzed the prostate motion characteristics and investigated methods to incorporate such knowledge into the registration optimization framework to improve robustness against local optima. Rigid motion of the prostate was analyzed adopting a mixture-of-Gaussian (MoG) model using 3-D TRUS images acquired at bilateral sextant probe positions with a mechanically assisted biopsy system. The learned motion characteristics were incorporated into Powell's direction set method by devising multiple initial search positions and initial search directions. Experiments were performed on data sets acquired during clinical biopsy procedures, and registration error was evaluated using target registration error (TRE) and converged image similarity metric values after optimization. After incorporating the learned initialization positions and directions in Powell's method, 2-D-3-D registration to compensate for motion during prostate biopsy was performed with rms ± std TRE of 2.33 ± 1.09 mm with ~3 s mean execution time per registration. This was an improvement over 3.12 ± 1.70 mm observed in Powell's standard approach. For the data acquired under clinical protocols, the converged image similarity metric value improved in ≥8% of the registrations whereas it degraded only ≤1% of the registrations. The reported improvements in optimization indicate useful advancements in robustness to ensure smooth clinical integration of a registration solution for motion compensation that facilitates accurate sampling of the smallest clinically significant tumors.