A comparative study was conducted to investigate the resulting tool wear and hole quality when drilling the stacks made of titanium (Ti) and carbon-fiber reinforced plastic (CFRP) versus CFRP only plate using micrograin tungsten carbide (WC) twist drills. The experiments were designed to first drill CFRP alone to create 20 holes. Then, CFRP mechanically stacked with Ti was drilled for the next 20 holes with the same drill bit. This process was repeated until drill bit failure. The drilling experiment was performed at two distinct speeds. Scanning electron microscope (SEM) and confocal laser scanning microscope (CLSM) were used for tool wear analysis. Hole size, hole profile, surface roughness, and Ti burrs were analyzed using coordinate measuring system, surface profilometer and optical microscope. The experimental results indicate that the Ti drilling accelerated flank wear while CFRP drilling deteriorated the cutting edge. Entry delamination, hole diameter errors, and surface roughness of the CFRP plate became more pronounced during the drilling of CFRP-Ti stacks when compared with the results from the drilling of CFRP only. Damage to CFRP holes during CFRP-Ti stack drilling may be caused by Ti chips, Ti adhesion on the tool drill margin or the increased instability as the drill bits wear.