Background: Recent influenza antiviral resistance studies reveal an alarming increase in both adamantanes and neuraminidase inhibitors (NAIs) resistant viral strains worldwide, particularly in Asia, Europe and the United States. Objectives: In this study, we have evaluated influenza virus resistance in Central and South America. Methods: Influenza viruses, isolated from symptomatic patients throughout Central and South America in 2005-2008 were analyzed for inhibitor resistance. The M2 and NA genes of influenza viruses were sequenced and resistance was inferred by comparison with published sequences and known resistant mutations. Results: Our results indicate that: (i) resistance to adamantanes was seen in the majority (95.5%) of the influenza A/H3N2 isolates but only in one isolate of the influenza A/H1N1 viruses; (ii) resistance to NAIs began to be detected in A/H1N1 isolates from Central America in 2008; and (iii) none of the influenza B viruses analyzed were resistant to NAIs. Conclusions: These findings suggest a limited effectiveness of influenza inhibitors due to the detection of resistance among A/H1 and A/H3 viruses. © 2009 Blackwell Publishing Ltd.