This study examined the role of marijuana smoking in the pathogenesis of human lung cancer by measuring DNA damage in alveolar macrophages (AM). The alkaline unwinding method was used to determine DNA single-strand breaks in AM lavaged from non-smokers [NS] and smokers of marijuana [MS], tobacco [TS] or cocaine [CS], either alone or in combination. DNA damage was related to superoxide anion (O2-) production by AM stimulated with phorbol myristate acetate (PMA) and to nitric oxide content of smoke using cellular nitrite (NO2-) concentrations. The percentage of double-stranded DNA present after alkaline unwinding was higher in AM of NS (41 +/- 5% [11]) and CS (41 +/- 4% [9]) versus that of MS (31 +/- 4% [8]), TS (35 +/- 3% [11]), MTS (26 +/- 4% [3]), and CTS (27 +/- 5%* [10]), mean +/- SEM [n], * = p < 0.1 vs. NS). PMA stimulated O2- production by AM from NS and CS was lower than that of other smokers, but the differences were not significant. O2- release, however, had an inverse correlation with DNA single-strand breaks (r = -0.38, p = 0.009). Nitrite content of AM from NS and CS was less than that of other smokers' cells (p < 0.1 for TS & CTS vs. NS), but DNA damage had no relationship to NO2- concentration. We conclude that AM recovered from MS, either alone or in combination with tobacco smoking, show a trend towards DNA damage. Studies utilizing a larger population should verify our findings and further define its relationship to enhanced oxidant production by macrophages.