Background The Mycobacterium tuberculosis load in the brain of individuals with tuberculous meningitis (TBM) may reflect the host's ability to control the pathogen, determine disease severity, and determine treatment outcomes. Methods We used the GeneXpert assay to measure the pretreatment M. tuberculosis load in cerebrospinal fluid (CSF) specimens from 692 adults with TBM. We sought to understand the relationship between CSF bacterial load and inflammation, and their respective impact on disease severity and treatment outcomes. Results A 10-fold higher M. tuberculosis load was associated with increased disease severity (odds ratio, 1.59; P =.001 for the comparison between grade 1 and grade 3 severity), CSF neutrophil count (r = 0.364 and P <.0001), and cytokine concentrations (r = 0.438 and P <.0001). A high M. tuberculosis load predicted new neurological events after starting treatment (P =.005, by multinomial logistic regression) but not death. Patients who died had an attenuated inflammatory response at the start of treatment, with reduced cytokine concentrations as compared to survivors. In contrast, patients with high pretreatment CSF bacterial loads, cytokine concentrations, and neutrophil counts were more likely to subsequently experience neurological events. Conclusions The pretreatment GeneXpert-determined M. tuberculosis load may be a useful predictor of neurological complications occurring during TBM treatment. Given the evidence for the divergent pathogenesis of TBM-associated neurological complications and deaths, therapeutic strategies to reduce them may need reassessment.