This is a case-control study conducted to examine the risk factors for multidrug resistance (MDR) among patients with pulmonary tuberculosis (TB) in four centers in Burkina Faso, West Africa: Ouagadougou, Bobo-Dioulasso, Gorom-Gorom, and Dori. Fifty-six MDR-TB cases and 304 controls were enrolled of which 40 MDR-TB cases and 222 controls were from Ouagadougou. The majority of cases were male, with 39 among MDR-TB cases and 205 in controls. The MDR-TB cases were aged from 14 to 75 years versus 11 to 75 years in the controls. The total risk assessment battery score was 11. Living outside of Burkina Faso (adjusted odds ratio [OR] = 0.017; 95% confidence interval [95% CI]: 0.001-0.325), known TB contact (OR = 0.045; 95% CI: 0.004-0.543), and patients with previous history of TB treatment (OR = 0.004; 95% CI: 0.000-0.0.052) were significantly associated with MDR-TB. TB contact and mainly previous treatment were the strongest determinants of MDR-TB. Also, living outside Burkina was a risk factor.