Abstract: Purpose Since the early 2010s, synthetic opioids have been on the rise in the illicit drug markets of North America and Europe, often as adulterants or substitutes for heroin. Ocfentanil, an early-onset fentanyl analogue, has been implicated in several fatalities, predominantly in Europe. W-18 is more prevalent in Canada and the United States. We present the findings for an unknown brown powder, advertised and purchased as heroin, which was sent to our laboratory for analysis in the framework of the Belgian Early Warning System on Drugs. Methods The sample was screened using liquid chromatograph coupled to a diode array detector and gas chromatograph coupled to a single quadrupole mass spectrometer. The findings were confirmed by liquid chromatography—triple quadrupole mass spectrometry. Results No heroin, 6-monoacetylmorphine or morphine was detected. Our analysis detected two new psychoactive substances: the synthetic opioid ocfentanil (1.6% m/m), and W-18 (0.3% m/m). The ocfentanil concentration was similar to those found in previous reports. No reference concentrations have been published for W-18. The presence of these two new psychoactive substances together in the same powder is unprecedented and prompted a warning by the Belgian Early Warning System on Drugs. Conclusion The unknown powder tested positive for ocfentanil and W-18. To the authors’ best knowledge this is the first case of the combined detection of these two new psychoactive substances in the same powder. We additionally demonstrate the advantage of building an in-house reference library beyond retention time.