View source for Main Hand vs. Off-Hand

Unless a character is Ambidextrous, they possess a Main Hand and an Off-Hand. 

==To-Hit Penalties==
An Off-Hand suffers a penalty depending on the relative size of the weapon. 
If the Off-Hand weapon has the same Size Category as the Character, it suffers a -4 penalty. For every size category above this, increase the penalty by 4. For every size category below this, decrease the penalty by 2 until 0. Consider Small characters to be Medium sized for this.

Thus, a Human wielding a Large weapon in their Offhand suffers a -8, -4 if they wield a Longsword (Medium), -2 if they wield a Short Sword (Small) or +0 if they wield a Dagger (Tiny).

==Skill Penalties==
Any Skill Check where the character is forced to use solely their Off-Hand when they would normally use on their Main-Hand suffers a -4 penalty. This does not apply, for instance, to a checks involved in disarming an opponent, but it would apply if a character was attempting to write legibly.

==Multiple Hands==
If a character possesses more than two hands, assume half of them are Main-Hands, rounding down, and the rest are considered are Off-Hands. If the character possesses only one hand from their race, unless stated otherwise, this is their Main-Hand. If the character possesses a prehensile tail, feet or other unique appendages not as suited for grabbing as a hand, these are not factored into determining how many Main-Hands vs. Off-Hands the character has - these are all Off-Hands.

If a species has nothing that constitutes a hand but may still have some form of a grip, such as a snake or a slime, this is considered an off-hand for purposes of using weapons but not for purposes of other skills or attacks.

==Unarmed Attacks==
Brawling, Wrestling and Natural Attacks are considered one Size Category smaller than the Character's effective size and thus suffer a -2 penalty if they are considered in any way 'off-handed' - this includes headbutts, kicks and bites. If a character has Proficiency in a Natural Attack, it no longer counts as being Off-Handed.