Background: Sophisticated cognitive and intellectual abilities are known to be attributed to the highly convoluted gyrencephalic brain in higher order mammals. Over the last several years, there have been many efforts to establish clinically relevant neuroimaging indicators of cognitive dysfunction in persons with multiple sclerosis (PwMS). Given that cognitive functions are highly linked to the frontal lobe (FL) gyri, we aimed at exploring the sensitivity of frontal gyrification measurement in predicting cognitive decline. Objectives: To assess the predictive value of the changes in gyrification index (GI) of the FL in relation to cognitive dysfunction in MS, and to compare it with standard measures of regional atrophy. Methods: As part of a cross-sectional study on cognitive function in MS, thirty eight participants had brain magnetic resonance imaging (MRI) studies within a month from the neuropsychological testing and 5 years before then. Retrospective verbal memory was measured using the Rey Auditory Verbal Learning Test (RAVLT) and prospective memory was assessed with the Memory for Intentions Test (MIST). Coronal T1 MRI studies were chosen to assess the volume and GI of the FL by a blinded experimenter using FreeSurfer software. The anterior horn of the lateral ventricle and the central sulcus were used as anatomical landmarks delineating the anterior part of the FL and the total FL, respectively. Results: There were no changes observed in the total FL volume over the 5-year follow-up time period. On the contrary, total GI was reduced (p<.01). This reduction was observed in both right and left FL and only the anterior left FL showed regional significance (p<.01). While FL total volume was not correlated with cognitive function, baseline GI predicted both RAVLT immediate (r=-.39, p<.01) and long-term delays (r=-.4, p<.01) and MIST (r=-.2, p<.01). Negative correlations were also observed at 5-year follow up with the RAVLT immediate (r=-.32, p<.01) and long-term delays (r=-.36, p<.01). Subjective measures of cognitive decline did not have any correlations with FL volume or GI. Conclusions: Our findings suggest that FL folding and hence cortical grey matter thickness and volume might be specifically vulnerable in PwMS. Furthermore, FL structural changes may serve as reliable indicators of cognitive decline throughout the course of MS. Therefore, establishing baseline MRI indices for PwMS is a powerful tool to understand structural mechanisms behind cognitive decline.