INTRODUCTION: Previous research has shown that heavy cannabis users develop tolerance to the impairing effects of Delta9-tetrahydrocannabinol (THC) on neurocognitive functions. Animal studies suggest that chronic cannabis consumption may also produce cross-tolerance for the impairing effects of alcohol, but supportive data in humans is scarce. PURPOSE: The present study was designed to assess tolerance and cross-tolerance to the neurocognitive effects of THC and alcohol in heavy cannabis users. METHODS: Twenty-one heavy cannabis users participated in a double-blind, placebo-controlled, three-way study. Subjects underwent three alcohol-dosing conditions that were designed to achieve a steady blood alcohol concentration of about 0, 0.5, and 0.7 mg/ml during a 5-h time window. In addition, subjects smoked a THC cigarette (400 mug/kg) at 3 h post-onset of alcohol dosing during every alcohol condition. Performance tests were conducted repeatedly between 0 and 7 h after onset of drinking and included measures of perceptual motor control (critical tracking task), dual task processing (divided-attention task), motor inhibition (stop-signal task), and cognition (Tower of London). RESULTS: Alcohol significantly impaired critical tracking, divided attention, and stop-signal performance. THC generally did not affect task performance. However, combined effects of THC and alcohol on divided attention were bigger than those by alcohol alone. CONCLUSION: In conclusion, the present study generally confirms that heavy cannabis users develop tolerance to the impairing effects of THC on neurocognitive task performance. Yet, heavy cannabis users did not develop cross-tolerance to the impairing effects of alcohol, and the presence of the latter even selectively potentiated THC effects on measures of divided attention.