During human latent tuberculosis infection, Mycobacterium tuberculosis likely resides within the nutrient‐starved environment of caseous lung granulomas. The stringent response alarmone (p)ppGpp is synthesized by Rel in response to nutrient starvation, thus enabling tubercle bacilli to restrict growth and shut down metabolism in a coordinated fashion. In this study, we investigated the virulence of a rel‐deficient M. tuberculosis mutant in the guinea pig model. Quantitative reverse‐transcription polymerase chain reaction was used to study the effect of (p)ppGpp deficiency on expression of key cytokine and chemokine genes in guinea pig lungs. The rel‐deficient mutant showed impaired initial growth and survival relative to the wild‐type strain. Loss of Rel was associated with the striking absence of tubercle lesions grossly and of caseous granulomas histologically. The attenuated phenotype of the rel‐deficient mutant was not associated with increased expression of genes encoding the proinflammatory cytokines interferon‐γ and tumor necrosis factor α in the lungs 28 days after infection.