A new Mozambican guideline for management of fever in HIV-infected adults requires malaria testing and systematic consideration of specific alternative diagnoses (eg, tuberculosis and bacterial infections) in addition to malaria. We conducted a prospective observational study of the guideline's performance. Of 258 HIV-infected subjects with axillary temperature ≥37.5° C or history of fever, 76.0% improved, 13.6% died or were hospitalized, and 10.5% were lost to follow-up. In multivariate analyses, factors associated with adverse outcomes were bacterial blood stream infection, syndromically diagnosed tuberculosis, lower CD4 T-lymphocyte count, no antiretroviral therapy, lower body mass index, lower hemoglobin, and nonprescription of antibiotics.