Abstract: Background: Different antimicrobial drugs inhibit functions of the microbial cells but, unfortunately, some of these drugs can also affect the host cells, including macrophages. Since these cells represent the baseline defense against microbial agents, it is important that they are fully activated. Materials and Methods: In the present study we investigated the effect of amphotericin B and fluconazole on the functions of peritoneal macrophages from Balb/c mice treated with these antimycotics. For each antimycotic the therapeutic dose used in clinical practice (calculated on the mouse body weight) and two-fold higher doses were administered intraperitoneally once a day for three consecutive days. The control group was treated with saline in the same way. Four different tests, candidacidal assay, nitroblue tetrazolium test, adherence capability and phagocytic capability, were used to determine macrophage functions. Results: Our results confirmed positive effect of high dose amphotericin B on phagocytic capability (31.00 ± 4.46%), metabolic changes (27.93 ± 6.63%) and adherence capacity (59.24 ± 8.67%). Lower doses of drug amphotericin B (2 mg/kg) significantly increased the adherence index of macrophages (71.99 ± 5.55%) and intensity of the NBT intracellular reduction (30.20 ± 3.83%). Maximum dose of fluconazole expressed significantly higher phagocytic index (30.77 ± 2.17%), metabolic changes (24.00 ± 4.07%) and candidacidal activities (27.73 ± 6.73%), while lower doses of fluconazole (15 mg/kg) significantly increased the adherence index of macrophages (75.58 ± 5.47%) as well as the phagocytic index (29.23 ± 2.40%). Other results were similar as in control group. Conclusion: Positive immunomodulatory effects of fluconazole and amphotericin B may be clinically relevant especially in compromised patients who are predisposed to opportunistic fungal infections and require a long-term antimycotic therapy. Synergistic action of macrophages and antimycotics can influence the course of disorders related to immune suppression.