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We evaluated the safety, tolerability and antiretroviral activity of β-D-2,6-diaminopurine dioxolane (DAPD; amdoxovir) with or without mycophenolate mofetil (MMF) in HIV-1 infection following extensive antiretroviral therapy (ART).Oral DAPD 500 mg twice daily with placebo or MMF 500 mg twice daily was added to failing ART. HIV-1 RNA viral load (VL) decline to week 2 was analyzed by intent-to-treat, using rank-based tests. Patients with VL decline > 0.5 log10 copies/ml at week 2 (virologic response, VR) optimized ART and continued therapy for up to 96 weeks.Forty adults with median VL 4.5 log10 copies/ml, median 184 CD4+ cells/μl, and a median of 6 nucleoside reverse transcriptase inhibitor (NRTI) mutations (range, 1–8) were randomized. Median VL reduction at week 2 was −0.26 log10 copies/ml (P < 0.0001). Response to DAPD/placebo (median −0.37 log10 copies/ml) was unexpectedly greater than to DAPD/MMF (median −0.23 log10 copies/ml), although this difference was not statistically significant (P = 0.59). MMF appeared to lower concentrations of DAPD and its metabolite dioxolane guanosine. Of 10 patients with VR (DAPD 7, DAPD/MMF 3), four persisted beyond week 24. VR was more frequent with ≤ 5 baseline NRTI mutations (P = 0.12) or < 4 thymidine-associated mutations (TAMs) without E44D or V118I (P = 0.08). Twenty-three patients received extended DAPD +/− MMF; five beyond week 24. Few adverse events were related to study medications.The addition of DAPD +/− MMF to failing therapy appears safe and well tolerated. DAPD had significant activity at week 2 (mean −0.35 log10) in heavily pretreated patients that was not augmented by MMF.