Objective. Recent studies indicate that naltrexone implant may be one of the effective pharmacological treatments for opiate dependence. However, nowadays many of addicts are polydrug dependent. The aim of the study was to evaluate the effectiveness of naltrexone implant in the treatment of opiate and amphetamine polydrug dependence. Material and methods. A 10-week randomized, double-blind, placebo-controlled trial with 100 patients dependent on opiates and amphetamines has been conducted. Subjects were randomized in 1:1 ratio to either naltrexone implant or identically looking placebo formulation group. Primary outcome measures were retention in the study, proportion of drug-free urine samples and improvement in the Clinical Global Impression (CGI) scale. Results. At week 10, the retention was 52% among patients with naltrexone vs. 28% among patients with placebo implant (p=0.01), and the proportion of drug-free urine samples was 38% vs. 16% (p=0.01), respectively. Fifty-six per cent of patients treated with naltrexone implant showed marked improvement on CGI compared with 14% of patients treated with placebo (p<0.001, NNT=3.95%, CI 2-4). Conclusion. Naltrexone implant administration resulted in higher retention in the treatment, decreased heroin and amphetamine use, and improved clinical condition of patients, providing the first evidence on effective pharmacological treatment of this kind of polydrug dependence.