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The appearance of COVID disease and the introduction of subsequent measures and specific medical treatments throughout the world in 2020 could have been expected to cause the drug content changes in the surface waters. We have studied the lower course of the Croatian Mrežnica River at three areas (rural, small town, and large town domains) in three periods (May 2020, April and September 2021). The applied method was liquid chromatography with tandem mass spectrometry, which enabled the screening of 256 compounds with 7-9% (19-24 drugs) being detected, depending on the sampling period. In the beginning of the pandemic, total quantity of drugs was much lower in the rural and small town domain (142-187 ng L- 1) compared to the large town (954 ng L-1), whereas by the autumn 2021 marked increase of drug levels in rural and small town areas was observed (443- 481 ng L-1). Increase was especially notable for analgesics: non-opioid (aminophenazon, acetaminophen, ibuprofen) and opioid (tramadol, oxycodone). In spring of 2020, nonopioids were detectable only in large town domain (94.3 ng L- 1), and their concentrations steadily increased throughout the pandemic (up to 172 ng L-1). In the vicinity of small town, sharp increase of nonopioids occurred already in spring 2021 (235 ng L-1) and in rural area in autumn 2021 (125 ng L- 1). The opioids appeared in the river water at all studied sites in the last sampling period (46-90 ng L-1). Contrary to analgesics, decrease in quantity was recorded for the stimmulants, i.e. coffeine and cotinine (nicotine metabolite), indicating less active socializing due to the COVID epidemiological measures.