We have recently described an enumeration method using luminescent M. paratuberculosis strain expressing the luxAB genes of Vibrio harveyi which replaces fastidious and costly CFU counting by plating. Here we have re-evaluated the effect of Slc11a1(formerly Nramp1) polymorphism on susceptibility against M. paratuberculosis, using this luminometric method. A series of inbred mouse strains were infected intravenously with luminescent M. paratuberculosis S-23 and monitored for bacterial replication in spleen, liver and lungs for 12 weeks. Results clearly indicate that - as for M. avium subsp. avium- innate resistance to M. paratuberculosis infection is genetically controlled by Slc11a1.In BALB/c, congenic BALB.B10 (BALB/c background, H-2^b), C57BL/6 and mutant C57BL/6^bg/bg mice (all Slc11a1^s) bacterial numbers in spleen and liver remained stable during the first 4 weeks of infection, whereas in DBA/2, (C57BL/6xDBA/2)F₁ and congenic C.D2 mice (all Slc11a1^r) bacterial number decreased more than 30 fold during the first month after infection. Both male and female mice displayed the genetic difference. At later time points, additional differences in bacterial replication were observed between the susceptible mouse strains, particularly in the liver. Whereas bacterial numbers gradually decreased more than one-hundred fold in C57BL/6 mice between week 4 and week 12, bacterial numbers remained more or less constant in BALB/c and mutant C57BL/6^bg/bgmice. Mycobacteria-specific IFN-γ responses developed earlier and to a higher magnitude in C57BL/6 mice than in BALB/c mice and were lowest in resistant C.D2 mice.