Introduction: Pneumonia and meningitis are important causes of morbidity and mortality in the immunocompromised patients. Resistance to cotrimoxazole (CTX) and other antimicrobial agents used for empirical treatment regimens is an important problem for both microbiologists and clinicians. CTX is the drug currently in use as a prophylaxis for patients on antiretroviral therapy. There is need to assess its efficacy and monitor any emergence of resistance by bacterial pathogens which may cause morbidity and mortality in the immunocompromised patients. Methodology: A laboratory based cross-sectional study was used on a sample 200 bacterial isolates isolated from patients with pneumonia and meningitis was carried out. Pathogenic bacteria isolated from sputum and CSF samples of pneumonia and meningitis patients at five study sites were collected for culture and antimicrobial sensitivity testing during the period January 2014 to April 2014. The efficacy of cotrimoxazole and other antimicrobial drugs was calculated in percentage, per bacterial genus level. Tables were used to show the results for antibiotic susceptibility patterns. Graphs were used to show the minimum inhibitory concentration results. Results: Pathogenic bacteria isolated from sputum, pleural effusions and bronchial washings of patients with pneumonia showed a high level of resistance to CTX. Generally, ciprofloxacin, gentamicin and ceftazidime were the most effective drugs against pathogenic bacteria isolated from patients with pneumonia. There was a high diversity of pathogenic bacteria isolated from CSF. S. pneumoniae was the most common organism isolated from CSF contributing 40% of the total. S. agalactiae was the second most common organism isolated from CSF contributing 17.5% of the total. All the isolates of S. agalactiae, H. influenzae, and Group D Streptococcus and S. pneumoniae were resistant to CTX. Tetracycline, doxycycline, chloramphenicol, ceftazidime, erythromycin and clindamycin were the most effective drugs against S. pneumoniae. Conclusion and Recommendations: Pathogenic bacteria isolated from patients with pneumonia and meningitis showed a high level of resistance to cotrimoxazole. Results of this study suggest that use of CTX as a prophylactic drug for patients with HIV may not be effective for prevention of bacterial pneumonia and meningitis. The low number of organisms collected from patients with meningitis was mainly due to the fact that most cases of meningitis were due to Cryptococcus neoformans infection. There is need to carry out a larger study which encompasses both bacterial and fungal meningitis.