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Objective: During the COVID-19 pandemic, anxiety in people with multiple sclerosis (PwMS) may have increased; however, little is known about the various factors which influenced this. We aimed to (a) identify the psychosocial modifiable associates of anxiety in PwMS in Ireland and the United Kingdom and (b) explore experiences of anxiety during the pandemic. Method: A cross-sectional survey was developed using public and patient involvement in 2021. This included measures of anxiety (Hospital Anxiety and Depression Scale [HADS-A]), social support (Multidimensional Scale of Perceived Social Support [MSPSS]), multiple sclerosis control self-efficacy (Multiple Sclerosis Self-Efficacy scale [MSSE]), exercise habits (Godin Leisure-Time Exercise Questionnaire [GLTEQ]), MS acceptance (Acceptance of Chronic Health Conditions scale [ACHC]), and intolerance of uncertainty (Intolerance of Uncertainty Scale-12 [IUS-12]), with open-ended questions asking about experiences of anxiety during COVID-19. A hierarchical regression analysis investigated the extent to which anxiety could be predicted by psychosocial modifiable factors after controlling for sociodemographic factors and multiple sclerosis (MS) type, while reflective thematic analysis was used to analyze open-ended responses. Results: 287 PwMS completed the survey, with 58% reporting that their anxiety had increased during the pandemic. In order of magnitude, self-efficacy (β = −.41), intolerance of uncertainty (β =.35), social support (β = −.21), and exercise habits (β =.19) significantly predicted variance in HADS-A scores (p <.01). Themes describing sources of anxiety included personal health concerns, social concerns, and responsibilities/additional external burdens. In contrast, some PwMS reported that anxiety had decreased during COVID-19. Conclusions: While the generality of findings may be limited due to a predominately female sample of PwMS living in the United Kingdom and Ireland, results have the potential to inform the development of targeted interventions in rehabilitation psychology to reduce anxiety in this population. Impact and Implications: This study provides a valuable insight into understanding the experience of anxiety in people with multiple sclerosis (PwMS). A strength lies in its mixed-methods approach, in that both a quantitative analysis of the predictors of anxiety along with a qualitative analysis of the experience of anxiety during the COVID-19 pandemic are described. While a number of participants indicated improvements in their levels of anxiety during the pandemic, the majority reported experiencing increases in anxiety during this time. Our qualitative analysis suggests that this was primarily attributed to concerns around health, social factors, and additional burdens placed on PwMS during the pandemic. Results point to a number of psychological, social, and lifestyle factors that may reduce the experience of anxiety in this population and which have the potential to meaningfully targeted in rehabilitation interventions. Notably, interventions designed to enhance self-efficacy and increase tolerance of uncertainty are promising directions for future research. Given that less attention has been paid to ways that anxiety can be reduced in the context of multiple sclerosis, these findings are valuable in informing the provision of supports of this group specifically, while findings also have implications for those living with other chronic illnesses and disabilities more generally. [ABSTRACT FROM AUTHOR]