Influenza is known to cause severe respiratory illness in HIV-infected adults, but there are few data describing the relationship between HIV infection and influenza in West African countries such as Ghana. We conducted a prospective cohort study in the Shai-Osudoku and Ningo Prampram districts of Ghana from 2014 to 2016. Beginning May 2014, 266 HIV-infected and 510 HIV-uninfected participants age 18 to 73 years were enrolled and monitored for 12 months. We observed 4 and 11 laboratory-confirmed influenza cases among HIV-infected and HIV-uninfected persons, respectively. The overall rate of laboratory-confirmed influenza among HIV-infected participants was 15.0 per 1,000 person years (PY) (95% CI, 0.3-29.80 per 1,000 PY), whereas that among HIV-uninfected participants was 21.6 per 1,000 PY (95% CI, 8.8-34.3 per 1,000 PY) (incidence density ratio, 0.70; P = 0.56). Our study found no significant difference in the incidence of laboratory-confirmed influenza-associated illness among HIV-infected and HIV-uninfected individuals in Ghana.