Immunstimulatory properties of Tramadol mainly affects natural killer cells [NK] , and T- lymphocytes production . No proved evidence that Tramadol affects HLA-DR expression from activated monocytes .This study evaluate a combined approach using I.M tramadol 1.5 mg/kg and I.V paracetamol 15 mg/kg used for treatment of postcraniotomy pain in patients with supratentorial space occupying lesions. The analgesic efficacy and immunological status were our subject of interest. 40 patients ASA I or II scheduled for elective supratentorial craniotomy divided into two groups: Group Paracetamol received paracetamol 15 mg/kg i.v. before end of surgery for postcraniotomy pain relief repeated 6 hours postoperative. Group paracetamol+ received same dose of paracetamol + tramadol 1.5 mg/kg i.m. started 1 hour before end of surgery and repeated 6 hours postoperative. Analgesic efficacy was assessed by visual analogue scale "VAS" at 3, 6, 12 and 24 hours postoperative. Immunological parameters measured were HLA-Dr expression and γ-interferon. Venous blood samples were withdrawn at 4-time points: Preoperative, intraoperative, first and third day postoperative. HLA-Dr expression mean values showed no significant difference inside and in between the two groups. In group paracetamol they were 87.27 ± 1.65 , 86.73 ± 1.79, 85.28 ± 2.33 and 88.12 ± 1.66 at do, doo , d1 and d3, respectively while in group paracetamol+, they were 86.17 ± 1.77, 87.96 ± 1.91, 89.19 ± 1.37 and 89.92 ± 1.81 at d0, d00, d1 and d3, respectively. While γ-interferon mean values significantly decreased after induction of anesthesia in both groups. They were 3.6 ± 0.33 versus 3.55 ± 0.33, 3.25 ± 0.36 versus 3.14 ± 0.44, 3.55 ± 0.29 versus 3.93 ± 0.35 and 3.7 ± 0.41 versus 4.21 ± 0.36 at d0, d00, d1 and d3 in group paracetamol versus group paracetamol+, respectively. γ-interferon release recovered earlier in group paracetamol+ (by first day postoperative) rather in group paracetamol (by third day postoperative). The "VAS" mean values were significantly lower in group paracetamol+ patients than in group paracetamol ; 2.4 ± 0.11 versus 3.2 ± 0.17, 2.55 ± 0.11 versus 3.65 ± 0.18, 2.05 ± 0.05 versus 2.45 ± 0.11 and 1.05 ± 0.08 versus 1.8 ± 0.16 at the 3rd, 6th, 12 and 24 hours postoperative, respectively. In Group paracetamol+, eight patients experienced nausea and two vomited once. Tramadol when combined to paracetamol have yielded a better analgesia for post craniotomy pain and an improved immunological profile as regards to increased levels of γ-interferon. Although it had a negative effect on HLA-Dr expression, no infectious complications were reported in this study.