Benthic macroinvertebrates are integral components of stream ecosystems and are often used to assess the ecological integrity of streams. We sampled streams in the upper Clear Creek drainage in the Klamath—Siskiyou Ecoregion of northwestern California in fall 2004 (17 sites) and 2005 (original 17 plus 4 new sites) with the objectives of documenting the benthic macroinvertebrate assemblages supported by the streams in the area, determining how those assemblages respond to environmental variables, assessing the biological condition of the streams using a benthic index of biotic integrity (IBI), and understanding the assemblages in the context of biodiversity of the ecoregion. We collected both reach-wide (RW) and targeted-riffle (TR) macroinvertebrate samples at each site. The macroinvertebrate assemblages were diverse, with over 150 genera collected for each sampling protocol. The macroinvertebrate assemblages appeared to be most responsive to a general habitat gradient based on stream size, gradient, flow, and dominance of riffles. A second important habitat gradient was based on elevation and dominance of riffles. A gradient in water quality based on concentrations of dissolved ions and metals was also important. Models based on these 3 gradients had Spearman's rank correlations with macroinvertebrate taxonomic composition of 0.60 and 0.50 for the TR and RW samples, respectively. The majority (>50%) of the sites were in good or very good biological condition based on IBI scores. The diversity of macroinvertebrate assemblages is associated with the diversity of habitats available in the Klamath—Siskiyou Ecoregion. Maintaining the aquatic habitats in good condition is important in itself but is also vital to maintaining biodiversity in this diverse and unique ecoregion.