The most frequent factors associated with selection of resistance at the community level and the generation of multidrug-resistant tuberculosis (MDR-TB) under epidemic conditions have been described in the last decades. These factors are multiple, and it is often a combination of these that has been implicated in the origin of MDR-TB epidemics in specific zones or countries. The analysis of and correct approach to the causes should be the first and most important step in the fight against this critical problem. However, it has never been investigated whether specific circumstances, even under adequate implementation of a National TB Control Programme (NTP), could lead to selection or amplification of resistance. The NTP should consider explanations for when there is no decline in MDR-TB rates even after appropriate control measures have been implemented. Under the special circumstances analysed in this article, the World Health Organization (WHO) Category I regimen can amplify resistance to rifampicin (in initial isoniazid-resistant cases) or ethambutol (EMB) + pyrazinamide (in initial MDR-TB cases). The WHO Category II regimen can also amplify resistance to EMB or streptomycin. The subsequent addition of the only second-line drugs available in many countries (fluoroquinolones and/or injectables) can worsen the situation and generate extensively drug-resistant TB. Strategies for minimising these risks of amplifying resistance are discussed in this article.