We encountered an autopsy case in which the cause of death was judged as poisoning by multiple drugs, including AB-CHMINACA, 5-fluoro-AMB, and diphenidine. The deceased was a 30-year-old man. The postmortem interval to autopsy was estimated to be 3.5 days. Femoral vein blood, right heart blood, left heart blood, urine, and eight solid tissues including adipose tissue were collected and frozen until analysis. Extraction of the three drugs, and internal standards phencyclidine and 5-fluoro-AB-PINACA was performed by a modified QuEChERS method, followed by analysis by liquid chromatography–tandem mass spectrometry. Because this study dealt with various kinds of human matrices, we used the standard addition method to overcome the matrix effects. Quantitation of all three compounds was only achieved for the adipose tissue, whereas the levels of 5-fluoro-AMB were below the lower limit of quantitation (about 1 ng/g or ml) in all other samples. AB-CHMINACA was quantitated for all solid tissues, but not for all body fluid specimens. Diphenidine showed high concentrations in all specimens; it was highest in the adipose tissue (11,100 ± 1,120 ng/g), an order of magnitude lower in other solid tissue specimens, and two orders of magnitude lower in body fluid samples. The results suggest that adipose tissue is the best specimen for detection of lipophilic drugs, such as AB-CHMINACA, 5-fluoro-AMB, and diphenidine, in their unchanged forms. In this poisoning case, diphenidine appeared to have played the major role in the cause of death, because the concentrations of diphenidine were much higher than those of the synthetic cannabinoids in all specimens tested. To our knowledge, this is the first report to document the presence of AB-CHMINACA, 5-fluoro-AMB, and diphenidine in actual postmortem specimens in a fatal poisoning case.