An ultrasonic surgical instrument, comprising: (a) an ultrasonic transducer; (b) a handle assembly supporting the ultrasonic transducer, wherein the handle assembly includes: (i) a housing; and (ii) an ultrasonic blade acoustically coupled with the ultrasonic transducer; (c) a clamp arm assembly including a clamp arm; (d) an operator input feature; and (e) a mechanical lockout assembly (216, 316, 416, 416') configured to switch between at least an unlocked configuration and a locked configuration, Wherein, when the handle assembly and the clamp arm assembly are not completely coupled together, the mechanical lockout assembly is in the locked configuration and the mechanical lockout assembly prevents one or more of: the operator input feature of rotating the clamp arm relative to the ultrasonic blade, thereby preventing the operator from clamping onto tissue by rotating the clamp arm relative to the ultrasonic blade; and the operator input feature of activating at least one energy control button disposed on the handle assembly preventing activation of the ultrasonic blade, and wherein, when the clamp arm assembly and the handle assembly are completely coupled together, the mechanical lockout is in the unlocked configuration and the operator is able to activate the instrument using the operator input feature. (a) an ultrasonic transducer; (b) a handle assembly supporting the ultrasonic transducer, wherein the handle assembly includes: (i) a housing; and (ii) an ultrasonic blade acoustically coupled with the ultrasonic transducer; (i) a housing; and (ii) an ultrasonic blade acoustically coupled with the ultrasonic transducer; (c) a clamp arm assembly including a clamp arm; (d) an operator input feature; and (e) a mechanical lockout assembly (216, 316, 416, 416') configured to switch between at least an unlocked configuration and a locked configuration, Wherein, when the handle assembly and the clamp arm assembly are not completely coupled together, the mechanical lockout assembly is in the locked configuration and the mechanical lockout assembly prevents one or more of: the operator input feature of rotating the clamp arm relative to the ultrasonic blade, thereby preventing the operator from clamping onto tissue by rotating the clamp arm relative to the ultrasonic blade; and the operator input feature of activating at least one energy control button disposed on the handle assembly preventing activation of the ultrasonic blade, and wherein, when the clamp arm assembly and the handle assembly are completely coupled together, the mechanical lockout is in the unlocked configuration and the operator is able to activate the instrument using the operator input feature. Wherein, when the handle assembly and the clamp arm assembly are not completely coupled together, the mechanical lockout assembly is in the locked configuration and the mechanical lockout assembly prevents one or more of: the operator input feature of rotating the clamp arm relative to the ultrasonic blade, thereby preventing the operator from clamping onto tissue by rotating the clamp arm relative to the ultrasonic blade; and the operator input feature of activating at least one energy control button disposed on the handle assembly preventing activation of the ultrasonic blade, and the operator input feature of rotating the clamp arm relative to the ultrasonic blade, thereby preventing the operator from clamping onto tissue by rotating the clamp arm relative to the ultrasonic blade; and the operator input feature of activating at least one energy control button disposed on the handle assembly preventing activation of the ultrasonic blade, and wherein, when the clamp arm assembly and the handle assembly are completely coupled together, the mechanical lockout is in the unlocked configuration and the operator is able to activate the instrument using the operator input feature.