OBJECTIVE To describe the long-term outcomes of treatment of AIDS-related Mycobacterium avium complex (MAC) bacteremia using a standard clarithromycin-based regimen. METHODS Retrospective study of patients with MAC bacteremia diagnosed between April 1992 and April 1995. METHODS An urban AIDS clinic METHODS One hundred seventy-six consecutive patients with MAC bacteremia. METHODS Clarithromycin 500 mg twice daily, ethambutol 800 or 1200 mg daily, and clofazimine 100 mg daily. METHODS Late treatment failure (defined as a positive blood culture more than 90 days after starting treatment), clarithromycin susceptibility of initial and treatment-failure isolates, DNA fingerprinting of isolates from treatment failures. RESULTS Two out of 176 (1.1%) baseline isolates were resistant to clarithromycin. One hundred and fifty-one patients were treated for MAC bacteremia, 144 (95%) with the standard regimen. Of the 117 patients who survived > 90 days after starting therapy, 25 (21%) met the criteria for late treatment failure. Of the 22 treatment-failure isolates available for susceptibility testing, 19 (86%) were resistant to clarithromycin. Therefore, 13% of patients treated using the standard regimen (19 out of 144) had treatment failure associated with the emergence of clarithromycin resistance. Using logistic regression, non-compliance was associated with treatment failure (P = 0.02). Fourteen out of the 17 (82%) evaluable paired isolates had identical DNA fingerprint patterns, whereas three pairs showed that a different strain of MAC was present at the time of treatment failure. CONCLUSIONS Initial resistance to clarithromycin was rare during this period. However, late treatment failure associated with the emergence of clarithromycin resistance was relatively common during long-term follow-up. Most late treatment failures represented emergence of clarithromycin resistance in the initial strain.