Non-medical drug injection is a major risk factor for HIV infection in Russia and Estonia. Multiple drug use (polydrug) has further been associated with increased harms. We compared HIV, injecting and sexual risk associated with polydrug use among people who injected drugs (PWID) in 2012–2013 in Kohtla-Järve (Estonia, n = 591) and St Petersburg (Russia, n = 811). Using latent class analysis, we identified five (poly)drug classes, the largest consisting of single-drug injectors among whom an opioid was the sole drug injected (56% of PWID). The four remaining polydrug classes included polydrug-polyroute injectors who injected and used opiates and stimulants (9%), opiate-stimulant poly-injectors who injected amphetamine-type-stimulants with a primary opiate (7%) and opiate-opioid poly-injectors who injected opioids and opiates (16%). Non-injection stimulant co-users were injectors who also used non-injection stimulants (12%). In multivariable multinomial regressions, all four polydrug classes were associated with greater injection risks than single-drug injection, while opiate-stimulant and opiate-opioid poly-injection were also associated with having multiple sex partners. Riskier behaviours among polydrug-injectors suggest increased potential for transmission of blood-borne and sexually-transmitted infections. In addition to needles/syringes provision, services tailored to PWID drug and risk profiles, could consider drug-appropriate treatment and sexual risk reduction strategies to curb HIV transmission.