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Studies on the distribution of multiple sclerosis (MS) carried out in Southern Europe in the last years have shown a significant increase in the frequency of the disease. A previous descriptive survey in the Republic of San Marino, northern Italian peninsula, published in 1984 established that this area is at high risk for MS. We updated the frequency estimates of the disease by adopting a complete enumeration approach. On 31 December 2005, 50 MS patients (36 women and 14 men) yieldeda crude prevalence rate of 166.7 per 100 000 (95% CI 123.7–220), 235.3 (95% CI 165–327.4) for women and 95.2 (95% CI 52–160) for men. The average incidence from 1990 to 2005 was 7.9 (95% CI 5.3–11.1) per 100 000, 11.7 (95% CI 7.6–17.3) for women and 3.9 (95% CI 1.7–7.7) for men. We did not detect any significant temporal trend over the study period. These results confirm that in San Marino the disease occurs more frequently than that suggested in the past and support the data on MS frequency in continental Italy. The marked increase in MS prevalence ratio is partly due to the increasing survival of patients and the accumulation of new incidence cases owing to the reduction in diagnostic latency for better quality of neurological diagnostic procedures. However, an increased incidence of the disease could be considered. [ABSTRACT FROM AUTHOR]