People who use the thumb in repetitive manipulation tasks are likelyto develop thumb related impairments from excessive loading at the base jointsof the thumb. Biologically informed wearable robotic assistive mechanisms canprovide viable solutions to prevent occurring such injuries. This paper tests thehypothesis that an external assistive force at the metacarpophalangeal joint willbe most effective when applied perpendicular to the palm folding axis in termsof maximizing the contribution at the thumb-tip as well as minimizing the pro-jections on the vulnerable base joints of the thumb. Experiments conducted usinghuman subjects validated the predictions made by a simplified kinematic modelof the thumb that includes a foldable palm, showing that: 1) the palm folding an-gle varies from 71.5◦to 75.3◦(from the radial axis in the coronal plane) for thefour thumb-finger pairs and 2) the most effective assistive force direction (fromthe ulnar axis in the coronal plane) at the MCP joint is in the range 0◦<ψ<30◦for the four thumb-finger pairs. These findings provide design guidelines for handassistive mechanisms to maximize the efficacy of thumb external assistance.