The objective of this study was to compare the effectiveness of Efavirenz and Nevirapine based Firstline HIV treatment in patients attending comprehensive care centre in Mombasa. This was a prospective comparative study. The target population was HIV positive adult patients eligible for HAART. A total of 251 patients were enrolled in the study and followed up for 12 months. All ARV naive patients with CD4 count < 350/ul with WHO stage 3 or 4 and eligible for HAART were randomly into Efavirenz and Nevirapine based regimens (D4T/3TC/EFV and D4T/3TC/NVP) and followed up for a period of twelve months. Laboratory tests were done for each patient every three months by testing for Haemoglobin, Liver enzyme test (ALT), Creatinine and CD4 cell count. The study showed that first-line regimens of Efavirenz and Nevirapine were effective in suppressing HIV/AIDS infection with improvement in CD4 count (P<0.05). There was also improvement in haemoglobin levels and body weight among the patients on both regimens in the study. However, elevation of ALT and Creatinine were noted in both treatment groups, but this did not warrant drug discontinuation (P>0.05). Efavirenz based regimen appeared to be superior to Nevirapine based regimen on CD4+ profiles and renal function (P<0.05). There was no significant difference in haemoglobin levels, body weight and ALT enzyme for patients on both treatment groups.The findings demonstrated that D4TC/3TC/EFV and D4TC/3TC/NVP combinations were safe, well tolerated and effective in suppressing HIV progression in advanced HIV infected patients.