Abstract Tacaribe virus is know to protect guinea pigs and primates against lethal challenge with Junín virus. A long‐term study on the effect of Tacaribe virus infection in the guinea pig was carried out to determine the extent of cross‐protection and whether antigen and/or viral persistence and tissue damage could be detected in immune animals. Viral titers, antigen expression in organs, and histologic lesions were sequentially searched for up to 540 days postinfection (pi). Neutralizing antibodies (Abs) and cross‐protection to Junín virus were evaluated up to 660 days pi. Tacaribe virus titers and antigen peaked at 7–10 days pi to become undetectable after 30 days pi, except for a transient viral recovery from salivary gland. Virus was undetectable by coculture at 365 and 540 days pi. No immunoglobulins or C 3 deposits were detected by immunofluorescence in brain or kidney at any stage, and histologic lesions were absent throughout. Anti‐Tacaribe and anti‐Junín neutralizing Abs were detected up to 660 days and full protection against challenge was achieved at 365 and 540 days, declining to 33% at 660 days pi. The results warrant consideration of Tacaribe virus as potential heterologous vaccine against Argentine hemorrhagic fever.