Gaucher disease, the most prevalent genetic disorder among Ashkenazi Jews, is characterized by significant phenotypic heterogeneity. Because seven mutations account for more than 96% of the disease alleles in this population, large-scale screening is feasible, and genotyping is commercially available. To date, only 400 Gaucher patients have been diagnosed in Israel, although 2,500 patients are predicted by gene frequency; hence, there is the probability that those uncovered by population screening will prove to be very mild or asymptomatic since these patients have generally escaped medical attention until now. We studied objective and subjective aspects in 68 asymptomatic/very mild patients, followed for a mean of 2.6 years, to assess the implications of identifying many more such patients if large-scale screening were to be implemented. We found there were no medically significant changes in disease severity during follow-up. The patients' subjective reports of their general health status were similar to those of normal subjects, and there were no significant changes in quality of life during follow-up. Our findings suggest that asymptomatic/mild Gaucher patients do not require frequent monitoring; there is no justification for "prophylactic" enzyme therapy in this group, and, hence, no rationale for large-scale screening in the Ashkenazi population. Furthermore, one needs to be concerned with the adverse effects of labeling large numbers of asymptomatic individuals as affected because of the potential for stigmatization and discrimination.