Candida esophagitis, a defining illness of acquired immunodeficiency syndrome (AIDS), requires systemic antifungal therapy. Candida albicans can become resistant to commonly administered azole antifungal agents. An attractive alternative is caspofungin, an echinocandin antifungal that has generally displayed predictable activity against C. albicans. We report the case of a 29-year-old woman with AIDS who developed recurrent esophagitis caused by a strain of C. albicans that showed reduced susceptibility to caspofungin (elevated minimum inhibitory concentration of 8 mg/L). Analysis of the strain revealed that it contained a serine-to-proline substitution at position 645 in the FKS1 gene. Clinicians who prescribe caspofungin to treat esophagitis caused by C. albicans should recognize the potential risk, albeit slight, for acquired resistance to caspofungin and possibly other echinocandin antifungal agents in the face of persistent disease. In patients who are refractory or unresponsive to caspofungin therapy, susceptibility testing and/or alternative therapy should be considered.