In this study we aimed to evaluate the effect of the combination of clarithromycin and four inhibitors of efflux pumps (EPIs), including berberine (BER), carbonyl cyanide m-chlorophenylhydrazone (CCCP), piperine (PIP) and tetrandrine (TET), against 12 Mycobacterium avium complex clinical isolates. The minimum inhibitory concentration (MIC) of clarithromycin showed at least a fourfold reduction in presence of BER (83% of total isolates), CCCP (67%), PIP (25%) and TET (75%). Our results showed that the EPIs tested are active against both clarithromycin susceptible and resistant isolates. In particular, among the six resistant isolates, TET reversed the resistance phenotype of three strains, BER of two strains, and CCCP and PIP of one strain. Overall, our findings show the importance of these compounds in increasing the efficacy of clarithromycin in MAC clinical isolates.