This study investigated sense making in multiple sclerosis (MS) and relations with illness, religious-spiritual beliefs and adjustment (life satisfaction, positive states of mind, depression, anxiety). Four hundred and eight persons with MS completed a questionnaire. Half the sample generated sense making explanations for their illness. Content analyses revealed 16 sense making themes. Participants who reported having a religious-spiritual belief were more likely to report sense making than those who did not have such a belief. Sense making was related to lower disability and disease severity and evidenced beneficial direct effects on positive adjustment outcomes and depression after controlling for illness and religious-spiritual belief.