The Lower North Shore region of the St. Lawrence River is home to a fish-eating population that displays an unusually high body burden of several organochlorines, including polychlorinated biphenyls (PCBs) and dioxin-like compounds (DLCs). We measured biomarkers indicative of liver enzyme induction and investigated the relationship with organochlorine body burden in adult volunteers from this population. We determined plasma concentrations of PCBs and chlorinated pesticides by high-resolution gas chromatography (HRGC) with electron capture detection. DLC concentrations were measured by the dioxin-receptor chemically activated luciferase expression (DR-CALUX) assay and in a subset of participants, by HRGC/high-resolution mass spectrometry. We measured cotinine, d-glucaric acid, and porphyrins in morning urine samples and determined liver CYP1A2 activity in vivo using the caffeine breath test. Neither DLC concentrations as measured by the DR-CALUX nor PCB-153 concentrations, the latter representing total PCB exposure, were correlated with biomarkers of effects. Smoking (morning urinary cotinine concentration) was positively related to CYP1A2 activity as measured by the caffeine breath test (p < 0.01). Liver CYP1A2 activity was in turn negatively correlated with PCB-105:PCB-153 and PCB-118:PCB-153 congener ratios (p < 0.05). Hence, despite the relatively high body burden of PCBs and DLCs in this population, only smoking had a significant correlation with biomarkers of hepatic enzyme induction. Our data are consistent with smoking-induced liver CYP1A2 activity altering heme metabolism and increasing the biotransformation of mono-ortho PCB congeners.