Background: The incidence of multiple sclerosis (MS) in Puerto Rico (PR) is higher than in other Latin American and Caribbean countries. Although the etiology of MS is largely unknown, in a majority of cases (> 90%), there is correlation with intrathecal inflammation demonstrated by the presence of oligoclonal bands (OCBs) in the cerebrospinal fluid (CSF). Interestingly, in some cases, these OCBs are not detected presenting a challenge to diagnosing physicians. Objectives: The aim of this study is to examine trends of OCB-negative MS on clinical outcome and to provide prevalence rate estimates in PR. Methods: Data from the PR MS Foundation’s registry was used to identify individuals diagnosed with MS between the years 2017 through 2019, using the 2017 revised McDonalds criteria. In addition, the number of relapses after diagnosis, the level of disability, and CSF analysis reports were evaluated. Prevalence rates were estimated. A total of 195 newly diagnosed MS cases were recorded and of those, 87 had CSF data and were included. To evaluate the relative contribution of the factors on relapses we used a model selection approach using Akaike Information Criterion to evaluate the fitness of the models. A total 16 different models were evaluated. Results: The OCB-negative MS prevalence rate for PR was determined to be 10%. A significant association between positive OCB-status and increased disability was reported. However, this relationship was only significant in females and not males, which may be due to the small sample size of males in the study. Similar results were found with the number of OCB bands, IgG synthesis rate, and IgG index. On the other hand, the presence of intrathecal inflammation was not associated with relapses after diagnosis. Lastly, 8 models were equally as good and it was determined that the largest coefficients that contribute to higher disability were increasing age, OCB-presence, and higher IgG index. Conclusions: Prevalence estimates of OCB-negative MS for PR were slightly lower than other LAC countries and consistent with global OCB prevalence rates. Similar to previous literature, our findings suggest that OCB-negative MS is associated with a lower disability score.