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Introduction: Asymptomatic persons infected with the parasites causing visceral leishmaniasis (VL) usually outnumber clinically apparent cases by a ratio of 4–10 to 1. We assessed the risk of progression from infection to disease as a function of DAT and rK39 serological titers. Methods: We used available data on four cohorts from villages in India and Nepal that are highly endemic for Leishmania donovani. In each cohort two serosurveys had been conducted. Based on results of initial surveys, subjects were classified as seronegative, moderately seropositive or strongly seropositive using both DAT and rK39. Based on the combination of first and second survey results we identified seroconvertors for both markers. Seroconvertors were subdivided in high and low titer convertors. Subjects were followed up for at least one year following the second survey. Incident VL cases were recorded and verified. Results: We assessed a total of 32,529 enrolled subjects, for a total follow-up time of 72,169 person years. Altogether 235 incident VL cases were documented. The probability of progression to disease was strongly associated with initial serostatus and with seroconversion; this was particularly the case for those with high titers and most prominently among seroconvertors. For high titer DAT convertors the hazard ratio reached as high as 97.4 when compared to non-convertors. The strengths of the associations varied between cohorts and between markers but similar trends were observed between the four cohorts and the two markers. Discussion: There is a strongly increased risk of progressing to disease among DAT and/or rK39 seropositives with high titers. The options for prophylactic treatment for this group merit further investigation, as it could be of clinical benefit if it prevents progression to disease. Prophylactic treatment might also have a public health benefit if it can be corroborated that these asymptomatically infected individuals are infectious for sand flies. Author Summary: To study the association between positive serology for VL among asymptomatic persons and progression to disease, we analyzed combined data from two different cohort studies in which over 32,000 subjects were enrolled. All subjects were screened for presence of antibodies to L. donovani with DAT and rK39. After an interval of 6–12 months, a second round of surveys was conducted in which seroconvertors were identified, i.e. persons seronegative at baseline that had become seropositive in the interval between surveys. We subdivided the subjects according to serologic titers scored as negative, moderately positive or strongly positive. During follow-up we observed that the risk of progressing to disease was not very much different between seronegative and moderately seropositive subjects, but strongly increased for high titer seropositive subjects. This pattern was true for the initial serology, and even more pronounced among seroconvertors. Given the strongly increased risk of progression to disease among those with high DAT or rK39 titers, these data raise the question whether prophylactic treatment would be beneficial. The case for prophylactic treatment would be further strengthened if it could be shown that asymptomatically infected individuals are infectious to sand flies. [ABSTRACT FROM AUTHOR]