Background Mapping the heterogeneity of high-risk drug users is necessary to target harm reduction measures and drug policy. The aim of this study was to find if and how risk factors of adverse health outcomes varied for subgroups among illicit drug users from 2010 to 2012 and explore whether harm reduction measures, low-threshold services and treatment met such health risks from 2010 to 2019. Methods We interviewed 413 drug users at low-threshold facilities in three Norwegian cities from 2010 to 2012, and 351 respondents had a full dataset. The inclusion criterion was use of amphetamines, cocaine, heroin or opioids during the previous 12 months. Latent profile analysis was applied to establish subgroups with different health risk profiles. City-specific as well as national drug-induced deaths (2010-18) and injecting-related infectious diseases (2010-2019) were applied as outcomes. Harm reduction measures, low-threshold services and treatment in Norway from 2010 to 2019 are described. Results Reporting amphetamines (68%), heroin (60%) and opioids (65%) last 30 days were frequent, while reporting of cocaine was not (14%). Frequent use, injecting and co-use of amphetamines, heroin, and other opioids (prescribed or illicit) was high. The latent profile analysis separated users into five subgroups. Time since debut of use of amphetamines, cocaine, heroin or opioids varied between groups, as did types of psychoactive substances used and dependence. Injecting practices varied from 51% to 97% in the subgroups. Harm reduction measures in Norway since 2010 have been targeted to reduce the high level of injecting practices and their health consequences. However, drug-induced deaths at the national level and in the cities of the interviewees did not decline up to 2018. HIV among people who inject drugs at the national level declined from 2010 to 2019, while Hepatitis B did not, and the result for Hepatitis C was inconclusive. Conclusions Even though harm reduction measures for high-risk drug users in Norway have been targeted to reduce the high level of injecting practices and other health risks found in five subgroups in our sample from 2010 to 2012, further measures to reduce such risks and their health consequences must be tailored.