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We examined CD4cell count and plasma viral load patterns among Botswana TDFFTC Oral HIV Prophylaxis Trial (TDF2 study) participants who seroconverted, comparing participants assigned to receive tenofoviremtricitabine with participants assigned to receive placebo. We also evaluated for antiretroviral drug resistance among the breakthrough HIV infections. Among nine seroconverters assigned to tenofoviremtricitabine and 24 to placebo, there were no significant differences in their CD4cell count or viral load profiles over time. Of the four participants who seroconverted on-study while receiving tenofoviremtricitabine, none became infected as a result of drug-resistant HIV; moreover, no resistance mutations emerged following seroconversion.