Two recent articles in The Lancet (Mermin et al. 2004; Chintu et al. 2004) report on trimethoprim-sulfamethoxazole (TMP/SMX) prophylaxis in HIV positive individuals and favour the respective intervention on a large scale as recommended by UNAIDS/WHO (UNAIDS/WHO 2000; UNAIDS/WHO 2004). Mermin et al. and Chintu et al. suggest that all individuals with clinical manifestations of HIV infection, including children of all ages, should receive TMP/SMX daily to stabilize CD4 cell counts, control the viral load, prevent hospital admission, and reduce mortality due to opportunistic infections. The authors raise, consequently, the issue of potential cross-resistance between TMP and pyrimethamine (PYR) and SMX and sulfadoxine (SUL). HIV-associated opportunistic infectious agents and Plasmodium falciparum are, together with Mycobacterium tuberculosis, the main infectious killers in sub-Saharan Africa, and strategies to fight one may confer severe disadvantages in treating or preventing another. Based on the observation that in vitro cross-resistance between TMP/ PYR and SMX/SUL may result from drug pressure (Iyer et al. 2001; Khalil et al. 2003), extensive application of TMP/SMX in areas of highHIV prevalence has the potential of readily increasing the degree of P. falciparum SUL/PYR resistance. This applies particularly to areas where intermittent preventive treatment (IPT) control strategies with SUL/PYR are currently being implemented and evaluated to prevent P. falciparum malaria (Schellenberg et al. 2001; WHO/UNICEF 2003). The problem is accentuated by our recent observation of a high prevalence of P. falciparum resistance markers in clinically healthy adults in Ghana in the absence of essential SUL/PYR drug pressure, but common TMP/SMXuse in bacterial infections (Marks et al. 2005). This would imply that not only in regions with existing, but also in those devoid of SUL/PYR pressure, resistance to these substances might arise in addition to preexisting levels of resistance. Routine TMP/SMX prophylaxis of HIV-associated opportunistic infections and SUL/ PYR based IPT would then considerably affect each other, also with regard to presumably more frequent occurrence of severe cutaneous adverse drug reactions such as toxic epidermal necrolysis and Stevens-Johnson syndrome. As a result of the high levels of resistance to chloroquine and SUL/PYR, several sub-Saharan countries have meanwhile changed their first-line treatment of uncomplicated P. falciparummalaria, and artemisinin-based combinations are now widely used. However, economic conditions must not be neglected. Although an official agreement on the costs of new first-line drugs of WHO with manufacturers of these drugs is effective, malaria treatment courses with artemisinin, e.g., artemether/lumefantrine cost US $0.90 (children) and $2.40 (adults), irrespective of distribution and retail expenses. In contrast, SUL/PYR malaria treatment is available for US $0.13/$0.25 (children/adults). Obviously, cheaper drugs will preferentially be applied in areas where antimalarial self-treatment, without attending health professionals, is common practice. These considerations stress the urgency of (i) further studying mechanisms that lead to cross-resistance between various antifolates, (ii) intensemonitoring of prevalence and spread of drug-resistant infectious organisms, (iii) probatory studies and evaluation of IPT with alternative drugs, including HIV-positive individuals, (iv) making affordable new first-line antimalarials, considering interactions with current treatment/prophylaxis policies in HIV-positive individuals, and (v) detailed analyses of the primary causes ofmortality, whichmay be either because ofHIV-associated opportunistic infections, malaria, or other conditions.