Abstract Background We compared adjunctive treatment with placebo, dexamethasone, anti-C5 antibodies, and the combination of dexamethasone plus anti-C5 antibodies in experimental pneumococcal meningitis. Methods In this prospective, investigator-blinded, randomized trial, 96 mice were infected intracisternally with 10 7 CFU/ml Streptococcus pneumoniae serotype 3, treated with intraperitoneal ceftriaxone at 20 h, and randomly assigned to intraperitoneal adjunctive treatment with placebo (saline), dexamethasone, anti-C5 antibodies, or dexamethasone plus anti-C5 antibodies. The primary outcome was survival during a 72-h observational period that was analyzed with the log-rank test. Secondary outcome was clinical severity, scored on a validated scale using a linear mixed model. Results Mortality rates were 16 of 16 mice (100 %) in the placebo group, 12 of 15 mice (80 %) in the dexamethasone group, 25 of 31 mice (80 %) in the anti-C5 antibody group, and 18 of 30 mice (60 %) in the dexamethasone plus anti-C5 antibody group (Fisher’s exact test for overall difference, P  = .012). Mortality of mice treated with dexamethasone plus anti-C5 antibodies was lower compared to the anti-C5 antibody-treated mice (log-rank P  = .039) and dexamethasone-treated mice (log-rank P  = .040). Clinical severity scores for the dexamethasone plus anti-C5 antibody-treated mice increased more slowly (0.199 points/h) as compared to the anti-C5 antibody-treated mice (0.243 points/h, P  = .009) and dexamethasone-treated mice (0.249 points/h, P  = .012). Modeling of severity data suggested an additive effect of dexamethasone and anti-C5 antibodies. Conclusion Adjunctive treatment with dexamethasone plus anti-C5 antibodies improves survival in severe experimental meningitis caused by S. pneumoniae serotype 3, posing an important new treatment strategy for patients with pneumococcal meningitis.