We screened tuberculosis (TB) contacts as an outbreak investigation with tuberculin skin test (TST) and interferon-gamma release assay (IGRA). We evaluated adverse events and TB incidence in all persons screened after rifampicin (RFP) prophylaxis, and specifically assessed the new TB cases in relation to initial TST and IGRA results. The 180 contacts were divided into four groups: TST+/IGRA+ (n = 101), TST+/IGRA- (n = 22), TST-/IGRA+ (n = 16), and TST-/IGRA- (n = 41). RFP treatment (4 months) was prescribed only to the TST+/IGRA+ group. Of 87 contacts who initiated prophylaxis, adverse events occurred in 21 contacts (24.1%) including hepatotoxicity (11.5%), flu-like syndrome (5.7%), and thrombocytopenia (3.4%). TB developed in two TST+/IGRA+ subjects after completion of prophylaxis, including one multidrug-resistant (MDR)-TB case during 21.8 months of follow-up. Adverse events were frequent, and development of TB including MDR-TB occurred after RFP prophylaxis.