An effective and selective, modular sample preparation method for the extraction of eight antimycotic drugs, belonging to three different chemical classes, from digested sludge samples is proposed. To this end, matrix solid-phase dispersion (MSPD) was on-line connected with a cationic exchanger solid-phase extraction (SPE) cartridge. Analytes were extracted from the MSPD syringe, which contained the freeze-dried sludge sample dispersed with C18 plus a clean-up layer of primary and secondary amine (PSA) sorbent, with 10 mL of methanol. This extract flowed also through the SPE cartridge, where target compounds remained trapped while neutral interferences are released. After discarding the MSPD syringe, analytes were recovered with 10 mL of methanol (0.5% in NH3) before LC-MS/MS determination using a hybrid quadrupole time-of-flight (QTOF) mass spectrometer furnished with an electrospray ionization (ESI) source. In comparison with previously published sample preparation methodologies, the developed approach greatly simplifies sample handling and reduces attenuation of ESI ionization for sample extracts when compared to standard solutions. The obtained absolute recoveries ranged between 70 and 118%, and the limits of quantification (LOQs) of the method varied between 5 and 8 ng g(-1). Four antimycotic drugs were ubiquitous in urban sludge samples, with maximum average concentrations (above 400 ng g(-1)) corresponding to clotrimazole (CTZ). The screening capabilities of the LC-QTOF-MS system demonstrated that the developed modular extraction and purification methodology might be useful for the selective extraction of other basic drugs (e.g., sertraline, amitryptiline, and amiodarone) from sludge.