Forty-three percent (12/28) of ciprofloxacin (CIP)-nonsusceptible respiratory isolates of Haemophilus influenzae were hypermutable, compared with 8.5% (3/35) in the CIP-susceptible control group (P=0.002). CIP-nonsusceptible mutants were obtained with hypermutable strains only; these mutants developed three resistance mechanisms in a step-by-step process: target modifications, loss of a porin protein, and increased efflux.