Sacramento splittail (Pogonichthys macrolepidotus) is a species of special concern in California, due to multiple anthropogenic stressors. To better understand the potential impact of contaminant exposure, adult splittail were captured from the Sacramento-San Joaquin River Delta (California, USA) and analyzed for histopathology and contaminant exposure. Organochlorine contaminants (PCBs, DDTs, dieldrin, chlordanes, and PBDEs) and trace metals (Ag, As, Cd, Co, Cr, Cu, Fe, Mn, Mo, Ni, Pb, Se, Sn, V, and Zn) were detected in the tissues of all fish. In many samples, human health screening values were exceeded for PCBs (83 of 90 samples), DDTs (32 samples), and dieldrin (37 samples). In contrast, thresholds for fish effects were rarely exceeded. Histopathological analysis indicated the presence of macrophage aggregates in gonads, kidneys, and liver and a high incidence of liver abnormalities. In the liver, observed effects were often moderate to severe for glycogen depletion (55 of 95 fish), lipidosis (hepatocellular vacuolation; 51 fish), and cytoplasmic inclusion bodies (33 fish). Correlations between histopathology and tissue contaminant concentrations were weak and inconsistent. Significant correlations were observed between histopathology indicators and reductions in fish size, body condition, lipid content, and liver weight. These results suggest that splittail histopathology varies as a function of health and nutritional status, rather than exposure to legacy organic and metal pollutants.