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Background: Health care providers are at risk of acquiring human immunodeficiency virus (HIV) infection from occupational exposure, with nurses being the most vulnerable. There is no data on the awareness of post-exposure prophylaxis (PEP) among nurses in Cameroon. This study aimed to assess the knowledge, practices of nurses regarding PEP for HIV and their determinants in Cameroon., Methods: A cross-sectional study was conducted between April and July 2013, and involved 80 nurses in a rural health district in the North West Region of Cameroon. Data was collected using a structured questionnaire and analysed using the SPSS software version 20., Results: In all, 73.7% of the participants had poor knowledge about PEP for HIV. Though many (83.8%) had heard about PEP, just 10 (12.5%) had received formal training on PEP for HIV. Only 24 (30%) and 20 (25%) knew the correct drug regimen and duration of treatment respectively. The majority (85%) considered themselves to be at risk of acquiring HIV at work, with 54 (67.5%) having experienced an exposure in the past, mainly while setting up intravenous lines (57.4%), recapping needles (37.0%) and during delivery (24.1%). Of those exposed, ten (18.9%) received PEP, which was started after 24 hours in 50%. In multivariable regression analyses, awareness of hospital policy [OR: 0.043 (0.005-0.404), p-value = 0.006] was associated with Good knowledge on PEP for HIV., Conclusions: The knowledge and practice of nurses on PEP for HIV in Cameroon is low. There is urgent need for training programmes and workshops to increase awareness, improve practice, and reduce the risk of HIV acquisition from work related activities among health care providers.