In this study, a direct contact membrane distillation process was used to achieve rejection of 25 pharmaceutically active compounds (PhACs) in water. The influence of natural organic matter (NOM), a common contaminant in waters that are used for water supply, on PhACs removal was investigated. Humic acid was used as an organic model in order to represent major constituents of NOM. Results indicated that flux decline slightly increased from 0 to 8% as HA feed concentration increased from 0 to 80 mg L-1. Flux decline was mainly associated with membrane fouling which added hydraulic resistance to the transfer of liquid water. Pore wetting was observed when HA concentration increased, which indicated changes in the hydrophobic character of the membrane. MD process showed a rejection of >= 99% for the 25 assessed PhACs for all HA concentration evaluated even at high permeate recovery rate (60%), whereas, 24 PhACs presented concentrations below limit detection. The retention of PhACs by MD membrane occurs predominantly by membrane rejection which is mainly governed by volatility and, to a lesser extent, by hydrophobia. The adsorption contribution to PhACs retention was low ( < 8%) and was significantly associated with positively charged compounds. Although the feed side of the membrane became hydrophilic due to the HA deposit, the PhACs retention by DCMD was not affected, which reinforces the robustness of the process and the ability to produce safe water. Thus, in general, DCMD is less influenced by the feed composition than nanofiltration or reverse osmosis, implicating in higher PhACs rejections.