The aim of this paper is to study a simulation-based experimental design to identify significant factors affecting the performance of the tier-to-tier shuttle based storage and retrieval system (SBS/RS). SBS/RS design is an automated warehousing technology mostly utilized for the storage of mini-loads. SBS/RS has emerged as a response to the recent order profile with low volume and wide variety and quick response. Although the traditional design of SBS/RS is comprised of multi-shuttles each dedicated in each tier of an aisle, there can be different designs in which shuttles can travel between tiers. We call this design as tier-to-tier SBS/RS where shuttles can travel between tiers by using a separate lifting mechanism located at an endpoint of each aisle. Note that in this new design, since shuttles are allowed to travel between tiers, there may be less number of shuttles running in the system. Hence, the shuttle's average utilization value might be larger compared to that traditional one where each tier has a dedicated shuttle. In this work, we study an experimental design to investigate which factors are statistically significant on a critical performance metric (i.e., average cycle time per transaction) in the studied tier-to-tier SBS/RS. First, we simulate the system by using the ARENA 16.0 commercial software and then implement a full factorial analysis. The results are analyzed in MINITAB 17.0 software.