The emergence of multidrug-resistant (MDR) Streptococcus pneumoniae complicates disease management. We aimed to determine risk factors associated with MDR invasive pneumococcal disease (IPD) in South Africa and evaluate the potential for vaccination to reduce disease burden. IPD data collected by laboratory-based surveillance from 2003 through 2008 were analyzed. Multidrug resistance was defined as nonsusceptibility to any three or more different antibiotic classes. Risk factors for multidrug resistance were evaluated using multivariable logistic regression. Of 20,100 cases of IPD identified, 3,708 (18%) had MDR isolates, with the proportion increasing from 16% (461/2,891) to 20% (648/3,326) (P < 0.001) over the study period. Serotypes included in the 13-valent pneumococcal conjugate vaccine (PCV13) accounted for 94% of MDR strains. Significant risk factors for MDR IPD included PCV13 (1,486/6,407; odds ratio [OR] of 6.3; 95% confidence interval [CI] of 5.0 to 7.9) and pediatric (3,382/9,980; OR of 12.8; 95% CI of 10.6 to 15.4) serotypes, age of <5 (802/3,110; OR of 2.0; 95% CI of 1.8 to 2.3) or ≥65 (39/239; OR of 1.5; 95% CI of 1.0 to 2.2) years versus age of 15 to 64 years, HIV infection (975/4,636; OR of 1.5; 95% CI of 1.2 to 1.8), previous antibiotic use (242/803; OR of 1.7; 95% CI of 1.4 to 2.1), previous hospital admissions (579/2,450; OR of 1.2; 95% CI of 1.03 to 1.4), urban location (883/4,375; OR of 2.0; 95% CI of 1.1 to 3.5), and tuberculosis treatment (246/1,021; OR of 1.2; 95% CI of 1.03 to 1.5). MDR IPD prevalence increased over the study period. The effect of many of the MDR risk factors could be reduced by more judicious use of antibiotics. Because PCV13 serotypes account for most MDR infections, pneumococcal vaccination may reduce the prevalence of multidrug resistance.