A surgical stapling instrument includes a staple cartridge that may be loaded with surgical staples, an anvil mounted to confront the staple cartridge for deforming staples driven theretoward, and advancer for advancing the staple cartridge from an open position toward the anvil to a closed position for clamping tissue to be sutured therebetween, and a driver for driving the staples from the cartridge toward the anvil through tissue clamped between the cartridge and the anvil. A trigger for operating the driver, and a safety mechanism linked to the advancer preventing the trigger from operating the driver when the cartridge is in the open position but permits the trigger to operate the driver only when the cartridge is in the closed position. In addition, a coupling mechanism can removably mount a head assembly and a handle assembly, with each assembly containing a portion of the advancer and driver. The coupling mechanism can also include a rotatable mechanism for permitting relative rotation between the handle assembly and the head assembly. The advancer includes a clamp lever that articulates first in the forward direction and then in a downward direction. The staple cartridge can include a housing loaded with at least one staple and a comb with at least one tooth. The comb is driven by the driver to drive the staple and can be of varying lengths to compliment the staple.