Tuberculosis and leprosy are the two most important mycobacterial diseases affecting humans. Although there are several similarities between the diseases (eg, both have long incubation periods and require long-term therapy with similar drugs), one difference is in the approaches to prophylaxis (ie, the prevention of disease among symptomless individuals with presumed low bacillary load). WHO recommends a single dose of rifampicin for leprosy post-exposure prophylaxis (PEP) whereas the recommended duration for tuberculosis preventive therapy (TPT) with rifampicin alone is 4 months (112 doses). Even the shortest approved TPT regimens involve combination therapy and are comparatively lengthy (either 28 daily doses or 12 weekly doses of rifapentine and isoniazid). In this Comment, we discuss the reasons for the difference in approach, how leprosy and tuberculosis research could develop a synergistic relationship, and the prospect of ultrashort regimens for tuberculosis prophylaxis.