BACKGROUND: Accurate diagnosis of latent tuberculosis infection (LTBI) in recently exposed HIV-infected tuberculosis (TB) contacts is a public health priority because of the high risk of progression to active TB but is hampered by the high background prevalence of LTBI in high-burden populations and poor sensitivity of tuberculin skin testing (TST) in HIV co-infection. METHODS: The prevalence of LTBI in 222 recent household contacts of TB cases and 176 household contacts of community controls without TB in Harare, Zimbabwe were compared using TST and interferon gamma enzyme-linked immunospot (ELISpot) responses to ESAT-6 (early secretory antigenic target-6) and CFP-10 (culture filtrate protein-10). TST and ELISpot results were correlated with markers of recent TB exposure and the impact of HIV co-infection was assessed. RESULTS: In this high-incidence population, the proportion of ELISpot-positive contacts was not significantly different from community controls. However, ELISpot, unlike TST, revealed a higher prevalence of LTBI in recent contacts of sputum smear-positive cases than in contacts of controls. ELISpot results correlated significantly with positive sputum smear and culture status of the index case (adjusted OR 2.40, CI 1.12 to 5.14), even in the subgroup of HIV-infected contacts (adjusted OR 5.36, CI 1.11 to 25.93). and were independent of contacts' HIV status. TST results were also associated with positive smear and culture status of the index case (adjusted OR 4.41, CI 1.82 to 10.67) but were negatively associated with contacts' HIV status (adjusted OR 0.25, CI 0.10 to 0.60). CONCLUSIONS: Contact investigations in high-burden populations should focus on contacts of sputum smear-positive cases in whom recent infection can be detected by ELISpot, even in the presence of HIV co-infection.