Introduction: A Wastewater Based Epidemiology approach was performed to estimate the drug consumption in Palermo city, the fifth largest city of Italy, and to investigate the variability of monthly drug loads in wastewater in different areas of the city, within a seven-months detection campaign at the two wastewater treatment plants of the city. Methods: Following a pre-treatment, 32 samples of wastewater were analyzed by liquid chromatography–tandem mass spectrometry. Results: We estimated a mean cocaine use in Palermo of 0.19 g/day/1,000 people, corresponding to 1.90 doses/1,000 people and cannabinoids use of 2.85 g/day/1,000 people, corresponding to 35.62 doses/1,000 people. Amphetamines residues in wastewater were always recovered in concentrations lower than the limit of quantification. Conclusion: Prevalence on cocaine and cannabinoids consumption allowed us to compare our data with those of other Italian and European cities and to evaluate how could vary the final estimates in different periods of a year.