We investigated whether or not mutations at codon 215 in the HIV reverse-transcriptase-encoding gene predicted a lower efficacy of didanosine therapy, as defined by survival of patients and change in CD4 cell counts in 121 HIV-infected, zidovudine-experienced patients. A trend for shorter survival, although not reaching significance, was observed for patients with HIV strains with the reverse transcriptase codon 215 mutation (P = 0.07), but this trend disappeared after adjustment for initial CD4 cell counts. During the first 3 months on didanosine therapy, the increase in CD4 cell counts was greater in patients who were wild type at codon 215 than in those with the mutation at codon 215 (P = 0.03). These data suggest that there was a better initial CD4 response to didanosine therapy in patients with HIV without the mutation at codon 215, but that this response did not translate into increased survival.