Artisanal gold mining (AGM) with metallic mercury has a long history in Ghana. It is believed to be over 2,000 years old. Today, AGM has escalated in a new dimension consuming about half of the country where gold lode deposits exist along riverbanks or rivers are alluvial-gold rich. The Pra River in southwestern Ghana is a site of on going application of metallic mercury in prospecting gold, and this paper examines mercury (Hg) contamination in the different environmental compartments in its watershed. Samples of water, sediment, soil and biota (i.e., human hair and fish) were collected from locations along the course of the river during the rainy and dry seasons of 2002 and 2003, respectively. Besides the obvious Hg point sources along the Pra and its tributaries, the obtained results show that Hg levels and speciation in the studied aquatic system are controlled by precipitation, which drives the hydrology and differences in flow regimes versus seasons. The seasonal difference in Hg speciation suggests that methyl mercury (MeHg) found in the aqueous phase and riverine sediments is likely of terrestrial origin where its production is favored during the rainy season by high soil water and organic matter content. The use of the enrichment factor (EF) for the assessment of sediment quality indicated moderate to severe contamination of surface sediments in the rainy season, while in the dry season, the EF index indicates nearly no pollution of surface sediments. Accordingly, most of the Hg introduced into this river system is likely transported to depositional downstream terminal basins (e.g. the river delta and the Gulf of Guinea). With regard to biota, Hg measured in hair in the dry period was higher than data obtained on samples collected during the wet period. This could be explained at least in part by the shift in diet as a result of abundance of fish in the local markets and the concurrent increase and more active fishing during the dry season. Mercury data obtained on a very limited number of fish samples collected during the dry period only are also presented.