14-Hydroxyclarithromycin, an active metabolite of clarithromycin, was compared for antimicrobial activity alone and in combination with the parent compound. The 14-hydroxyclarithromycin potency was comparable to that of clarithromycin, but was more active against Haemophilus influenzae (MIC50, 1 microgram/ml). Combination MICs at pharmacokinetic ratios produced end points equal to the most active component of the combination. However, checkerboard MICs and kill-curve studies suggested enhanced interactive effects. Partial synergy and additive interactions were demonstrated in 96% of strains tested with synergy (partial) most often observed among the Enterococcus faecalis, H. influenzae, and staphylococci. To determine the best in vitro test methods for predicting the value of 14-hydroxyclarithromycin, combination disks or ratio MIC tests may not be practical. A modification of the proposed clarithromycin-susceptible breakpoint (less than or equal to 2 micrograms/ml) upward to less than or equal to 4 micrograms/ml (greater than or equal to 14 mm) was suggested to recognize the additional activity contributed by the 14-hydroxy metabolite. This modification should be applied, limited to susceptibility tests of H. influenzae and possibly the enterococci.