Because multiple sclerosis (MS) affects many life areas, it is important to know how participation and autonomy are associated with the perceived impact of MS on everyday life.To investigate how perceived quality of life, disease impact, gender, and disease severity predict participation and autonomy in people with MS.Cross-sectional study in which structural equation modeling was used to evaluate relationships between measured variables.Outpatient clinics in three areas and one inpatient rehabilitation center in Finland.Convenience sample of 194 people with MS.Participants completed the Impact on Participation and Autonomy (IPA), the World Health Organization Quality of Life-Brief measure (WHOQOL-BREF), and the Multiple Sclerosis Impact Scale (MSIS-29). The Expanded Disability Status Scale (EDSS) was administered by a neurologist.The final model showed good fit to the data. All the goodness-of-fit indexes except χ² supported the model, χ²(30, N = 194) = 46.729, p < .026; comparative fit index = .983; Tucker-Lewis index = .969; root mean square error of approximation = .054; standardized root mean square residual = .039. Quality of life (WHOQOL-BREF) and the impact of multiple sclerosis (MSIS-29) were the main predictors of participation and autonomy. Disease severity influenced only the IPA Autonomy Indoors domain. Gender was not associated with participation and autonomy.Experiences of participation and autonomy appear to be closely associated with perceived quality of life and impact of the disease. Findings support the importance of assessing participation and autonomy and planning interventions using this information.The IPA appears to be an appropriate measure for assessing participation and autonomy and planning occupational therapy interventions for people with MS. In particular, environmental factors affecting participation and autonomy should be considered when planning interventions to promote participation and autonomy.